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Purpose Age at breast cancer diagnosis not only predicts clinical outcome, but also indicates distinct molecular features thus we can choose the most appropriate treatment strategies. Yet little is known about the molecular profile of young and elderly triple negative breast cancers (TNBCs). Methods Clinical, genomic and transcriptome features of young ( Results In this study, 50, 354 and 69 patients were Conclusions TNBCs of different age had distinct clinical and molecular features. We should pay attention to that nearly half of the TNBCs diagnosed at 65 years-old or later were not basal-like cancers but a special group with positive AR staining. Taking together with the higher fibrosis/MES proportion in elderly TNBC, we should reconsider the benefit of specific treatment strategies (like neoadjuvant chemotherapy) in these patients. The young TNBCs were characterized by activated cell cycle, elevated nucleotide metabolism (especially TYMS expression and corresponding pyrimidine metabolism) and enhanced DNA damage (especially HRD). These molecular features supported the aggressive phenotypes of young TNBC, while also provide us with potential therapeutic strategies. Citation Format: Ma D, Jiang Y-Z, Xie M-D, Xiao Y, Zhao S, Shao Z-M. Multi-omics profiling reveals distinct molecular features in young and elderly triple negative 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 P3-08-11.

Background: Metastatic regional lymph nodes (LN) is a strong predictor of worse long-term outcome after resection of breast cancer. This study aimed to compare the prognostic performance of American Joint Committee on Cancer (AJCC) N stage relative to lymph node ratio (LNR), log odds of metastatic lymph nodes (LODDS), number of removed lymph nodes (NRLNs), and number of negative lymph nodes (NNLNs) in breast cancer patients. Methods: All of the breast cancer patients who underwent surgery between 2004 and 2012 were identified from the Surveillance, Epidemiology, and End Results database. Restricted cubic spline functions were used to characterize the association between continuous variables and the risk of death and determine the optimal cut-off points. The Cox proportional hazards models were constructed, and the relative discriminative abilities of the different LN staging systems were assessed using the Akaike's Information Criterion (AIC) and the Harrell's concordance index (C-index). Results: A total of 264,096 breast cancer patients were enrolled, and 177,598 (67.2%) had no lymph node metastasis, whereas 86,498 (32.8%) had lymph node metastasis. 187,785 (71.1%) patients had a limited number of LNs harvested (NRLN Conclusions: Although LNR assessed as a continuous variable was the most potent method to stratify patients regardless of LN status, the prognostic superiority of LNR is confounded by a limited LN harvest. LODDS was a better and more powerful predictor of survival when patients were LN positive, especially among those patients with either very low or high LNR. Citation Format: Gong Y, Ji P, Jiang Y-Z, Hu X, Shao Z-M. Comparing prognostic performance of different lymph node staging systems among patients 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 P2-08-36.

Purpose: Chemotherapy remains the only systemic treatment option for patients with triple-negative breast cancer (TNBC). However, due to the heterogeneity of TNBC, not all patients benefit from chemotherapy, especially those with early-stage disease. In order to improve prognostic assessment and reduce unnecessary adjuvant systemic therapy in these patients, we have developed a novel seven-gene signature. Experimental Design: With the ComBat method, we integrated the results from 150 transcriptome microarrays samples and 246 RNA-seq samples of early-stage TNBC patients, and identified mRNAs associated with recurrence-free survival (RFS) using Lasso-Cox model, We further analyzed these TNBC samples and compared them with 60 paired normal breast tissues (40 samples from RNA-seq and 20 samples from microarrays) to identify tumor-specific mRNAs. Twenty-one overlapped mRNAs of the RFS-associated mRNAs and the tumor-specific mRNAs are selected as candidate mRNAs. An additional 371 samples of frozen primary tumors were then collected from early-stage TNBC patients (mean follow-up of 45 months) and randomly divided into two sets: a training set (n = 186) and a validation (n = 185) set. Expression level of candidate mRNAs in these samples were measured using RT-qPCR assays, and a seven-gene signature was built through all subset regression in the training set. The prognostic and predictive accuracy of our signature was tested in the validation set and other public databases (GSE5327, GSE2034 and METABRIC). Results: Twenty-one candidate mRNAs were identified in early-stage TNBC patients, from which we developed a novel seven-gene signature (recurrence risk score [mRNA signature] = 1.108*TMEM101 - 0.213*KRT5 - 0.315*ACAN - 0.464*LCA5 + 0.446*RPP40 - 0.373*LAGE3 - 0.257*CDKL2). Patients in the training set were classified into high- or low-risk group based on our seven-gene signature and an optimum cut-off score derived from x-tile. The patients in high-risk group were more likely to suffer from recurrence (HR, 2.718; 95% confidence interval [CI], 1.928–3.726, P= 0.001), and a time-dependent receiver operating curve showed that the seven-gene mRNA signature had a better prognostic value than the clinicopathologic risk factors in both training set and validation set. The prognostic and predictive accuracy of the signature was also validated in the METABRIC and two other public GEO databases (GSE5327 and GSE2034). The time-dependent receiver operating curve showed that this signature had an area under the curve (AUC) of 0.742 (95% CI, 0.705-0.773) in METABRIC, 0.716 (95% CI, 0.682-0.739) and 0.723 (95% CI, 0.683-0.756) in GSE5327 and GSE2034 respectively. Conclusion: In this study, we developed a novel seven-gene signature which can provide additional prognostic information and may guidance in identifying early-stage TNBC patients eligible for adjuvant therapy or reduction of chemotherapy. To our knowledge, this is the first study investigating the prognostic potential of mRNA signature in early-stage triple-negative breast cancer. Our novel signature may provide an opportunity for de-escalating treatment in early-stage TNBC patients in the future. Citation Format: Ren Y, Jiang Y, Zuo W, Xu X, Jin X, Ma D, Shao Z. A novel seven-gene signature predicts prognosis in early-stage triple-negative 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 P2-08-33.

Background Triple positive breast cancers (TPBCs), i.e. estrogen receptor-positive (ER+)/ progesterone receptor-positive (PR+)/ human epidermal growth factor receptor 2-positive (HER2+) breast cancers, constitute a therapeutic challenge due to the functional crosstalk between the hormone receptors and HER2 pathways. The intrinsic molecular subtyping of TPBCs has rarely been studied and may have implications for the prognostic evaluation and therapeutic decision-making. Methods Our study included four cohorts of patients with TPBC. The first one consisted of 82 patients from The Cancer Genome Atlas (TCGA). The second and third ones were from two publicly available microarray datasets (GSE2603 and GSE2109) and included 37 and 30 patients respectively. The forth one comprised 165 patients from Fudan University Shanghai Cancer Center. First, we examined the PAM50 intrinsic subtypes of TPBCs in the first three cohorts. Then, we tried to find several differentially expressed genes (DEGs) between luminal A and the other subtypes. In cohort 1, we identified DEGs using LIMMA. In cohort 2 and 3, we further filtered and validated them using Wilcoxon's rank sum test. We also performed Receiver operating characteristic analyses to evaluate the accuracy of candidate DEGs in identifying TPBCs of luminal A subtype and determined the top 3 DEGs according to the area under the curve. Finally, in cohort 4, we detected the expression of these 3 genes by immunohistochemical (IHC) staining of tissue sections, defined a group of luminal A-like TPBCs and examined the prognosis and effect of adjuvant trastuzumab for them. Results The distribution of PAM50 intrinsic subtypes of TPBCs was shown as follows. The three genes that exhibited the highest accuracy in identifying TPBCs of luminal A subtype were STC2, BCL2 (highly expressed in luminal A subtype) and MKI67 (lowly expressed in luminal A subtype). In cohort 4, we defined a group of luminal A-like TPBCs as TPBCs with low expression of MKI67 as well as high expression of STC2 and/or BCL2. Compared with patients with non-luminal A-like TPBC (n = 110), those with luminal A-like TPBC (n = 55) had better disease-free survival (DFS) in both univariate (Log-rank P = 0.029) and multivariate analyses (hazard ratio = 0.25, P = 0.025). In the group with non-luminal A-like TPBCs, patients treated with trastuzumab (n = 67) showed better DFS than those not treated with it (n = 43) (Log-rank P = 0.019), while in the group with luminal A-like TPBCs, there is no difference in DFS between patients treated with trastuzumab (n = 22) and those not treated with it (n = 33) (Log-rank P = 0.993). PAM50 intrinsic subtypes of TPBCsPAM50 intrinsic subtypeCohort 1Cohort 2Cohort 3 N (%)N (%)N (%)Luminal A43 (52.4)15 (40.5)13 (43.3)Luminal B28 (34.1)17 (45.9)12 (40.0)HER2-enriched9 (11.0)2 (5.4)3 (10.0)Normal-like1 (1.2)2 (5.4)1 (3.3)Basal-like1 (1.2)1 (2.7)1 (3.3) Conclusions TPBCs are heterogeneous in terms of intrinsic molecular subtype. Evaluating the expression of STC2, BCL2 and MKI67 by IHC staining can help us to conveniently identify a group of luminal A-like TPBCs. Patients with this group of TPBCs have relatively good prognosis and may only gain limited benefit from adjuvant trastuzumab. Citation Format: Zhao S, Jin X, Jiang Y-Z, Shao Z-M. Identification of luminal A-like subgroup among ER+/PR+/HER2+ breast cancers and its clinical implications [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 P3-07-12.

This abstract was not presented at the conference. Citation Format: Liu Y, Chen S, Jiang Y, Wu J, Shao Z. 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 P4-08-18.

This abstract was withdrawn by the authors. Citation Format: Jiang Y-Z, Ma D, Suo C, Shi J, Xue M, Stover DG, Verschraegen C, Kaklamani V, Wang P, Shi L, Huang W, Shao Z-M. Withdrawn [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 P3-07-07.

LncRNA differentiation antagonizing non-protein coding RNA (DANCR) is an oncogene in various malignant cancers, including hepatocellular carcinoma (HCC). Autophagy is an intracellular self-digestion mechanism that accelerates the progression of HCC via promoting cell survival. However, the role of lncRNA DANCR in HCC, and the mechanism of lncRNA DANCR in the regulation of autophagy in HCC remains unknown. Therefore, the aims of this study are the investigation of the role of lncRNA DANCR in HCC, and the exploration of the molecular mechanism of lncRNA DANCR in regulating autophagy of HCC cells.In this study, the expression of lncRNA DANCR, miR-222-3p, and autophagy-related gene 7 (ATG7) was detected by qRT-PCR. The cell proliferation and colony formation were measured by Cell Counting Kit-8 (CCK-8) assay and colony formation assay. And the autophagic flux was evaluated by mRFP-GFP-LC3B reporter. The autophagy related proteins were analyzed by Western blotting. Besides, the relationship between lncRNA DANCR and miR-222-3p, as well as between miR-222-3p and ATG7, was determined by Dual-Luciferase reporter system.We found high expression of lncRNA DANCR and ATG7, and low expression of miR-222-3p in HCC tissues and cell lines. And lncRNA DANCR positively correlated with poor survival of HCC patients. Moreover, the knockdown of lncRNA DANCR inhibited cell proliferation and autophagy of HCC cells. And we predicted and proved that lncRNA DANCR induced cell proliferation, colony formation and autophagy by increasing ATG7 and suppressing miR-222-3p.Our study demonstrates the promoting role of lncRNA DANCR in HCC, and indicates the regulatory effects of lncRNA DANCR on regulating autophagy of HCC.

Luminal breast cancer is the most common subtype of breast cancer, representing more than 60% of all breast cancers. Endocrine resistance and late recurrence are two challenges in the treatment of luminal breast cancer. To overcome endocrine resistance in multiple levels, high-dose-fulvestrant can inhibit estrogen-receptor (ER)-dependent pathways, while targeted drugs can block ER-independent pathways.To reduce the risk of late recurrence in luminal breast cancer, recurrence prediction model should be formed. For patients with high risk of late recurrence, extended endocrine therapy, combination of ovarian function suppression (OFS) or vascular endothelial growth factor (VEGF) inhibitor could be utilized. Based on the challenges of the treatment, scientific research achievements can be used in clinical practice, and finally optimize the clinical treatment strategy.Luminal型乳腺癌是最常见的乳腺癌分型，约占乳腺癌的60%以上，其治疗难点在于内分泌治疗耐药和远期复发。针对内分泌治疗耐药，应根据不同的通路机制从多角度入手，可用高剂量氟维司群抑制雌激素受体通路，或加用各类靶向药物阻断非雌激素受体通路。为降低Luminal型乳腺癌远期复发的风险，则应建立复发预测模型，延长高危复发患者内分泌治疗的时限，加用卵巢去势或血管生成抑制剂。以Luminal型乳腺癌治疗难点指导科学研究，将研究成果回归临床应用，最终优化临床治疗策略。.

Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. We used RNA-Seq to analyze the transcription level of each HERV loci across the genome in eight pairs of triple negative breast cancer (TNBC) and normal breast tissues. We identified one LTR70, which we dubbed TROJAN, was a TNBC related HERV. We also found that HERVs could not be researched as families because each members from the same family had different expression patterns in TNBC. TROJAN promoted proliferation and invasion in TNBC cells and indicated poor outcomes in patients. Here, we confirmed that TROJAN regulated the progression of TNBC through multiple mechanisms, with ZMYND8, a metastasis-repressing factor, being one of the targets of TROJAN. TROJAN could bind to ZMYND8, promoting its degradation through ubiquitin-proteosome system, and downregulated the transcription level of EGFR, thus stimulating the metastasis of TNBC. The association of TROJAN, ZMYND8, and EGFR was subsequently confirmed in clinical samples. Furthermore, our study verified that the therapeutic delivery of antisense oligonucleotides targeting TROJAN significantly suppressed metastasis of TNBC in vivo. In conclusion, TROJAN promotes the progression of breast cancer and serves as a potential therapeutic target in TNBC. Citation Format: Jin X, Xu X-E, Jiang Y-Z, Shao Z-M. Human endogenous retrovirus TROJAN promotes triple negative breast cancer progression and represents a potential therapeutic target [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 P3-06-06.

Background: Estrogen receptor positive/ progesterone receptor negative/ human epidermal growth factor receptor 2 negative (ER+/PR-/HER2-) tumors define a distinct subtype of ER+ breast cancer, characterized by poor response to endocrine therapy and poor prognosis. The genomic landscape of ER+/PR-/HER2- tumor has yet to be systematically studied,and driver events for tumor progression and endocrine resistance with loss of PR expression are yet to be identified. Methods: We assessed 13,410 ER+/PR-/HER2- patients from Surveillance, Epidemiology, and End Results (SEER), the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) for clinicopathologic characteristics, survival and genomic analyses. Patients were divided into endocrine-resistant and endocrine-sensitive groups using an endocrine therapy sensitivity score [(0.8*ER+1.2*PGR+BCL2+SCUBE2)/4], and we further explored genomic events enriched in the endocrine-resistant group. Results: Clinicopathologic features and survival outcomes of ER+/PR-/HER2- patients were worse than ER+/PR+/HER2- in SEER and METABRIC cohort. The genomic landscape of ER+/PR-/HER2- tumors revealed them to have more aggressive properties, like a higher percentage of luminal B (29-35%) and basal-like (4-16%) subtypes; more intClust subtypes with high genomic instability (intClust1, 6); more TP53 mutation and less PIK3CA mutation; and more copy number variation events. ER+/PR-/HER2- tumors have more focal amplification events, including 8p11.23 (ZNF703) and 17q23.1 (RPS6KB1) and more focal deletion events, such as 17q21.31 (BRCA1) and 14q24.3 (MLH3). Pathifier pathway analyses showed that up-regulated pathways in ER+/PR-/HER2-tumors included those associated with biosynthesis, metabolism, drug resistance and DNA replications (FDR Citation Format: Liu X, Ma D, Jiang Y-Z, Liu Y-R, Yu K-D, Shao Z-M. Clinicopathologic characteristics and genomic essence analyses revealed estrogen receptor positive, progesterone receptor negative and human epidermal growth factor receptor 2 negative breast cancer to be more basal-like and endocrine resistant [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 P2-06-03.

Background The microenvironment phenotypes strongly affect the immunotherapeutic strategies for triple-negative breast cancer (TNBC). Although the multi-omics profile of TNBC has been comprehensively characterized, few studies have focused on the microenvironment phenotypes of TNBC. Methods With multi-omics data for the largest single-center TNBC cohort (n=386), we first established a TNBC-specific microenvironment cell signature. We further used single sample gene set enrichment analysis to calculate the relative number of microenvironment cell subsets in each sample. Then, we performed k-means clustering to classify the TNBC microenvironment phenotypes into heterogeneous clusters. Furthermore, we systematically analyzed the extrinsic and intrinsic immune escape mechanisms of different TNBC microenvironment clusters. In addition, we explored genomic alterations that might decrease immune infiltration in certain TNBC microenvironment clusters. Results We classified the TNBC microenvironment phenotypes into three heterogeneous clusters. Cluster 1 (type 1 “cold tumor”) had low microenvironment cells infiltration. Cluster 2 (type 2 “cold tumor”) was characterized by resting innate immune cells, fibroblasts and endothelial cells infiltration. Cluster 3 (“hot tumor”) was featured by adaptive immune cells infiltration. Analysis of immune escape mechanism revealed that an incapability to attract innate immune cells (resulting in failure of adaptive immunity) led to immune escape of cluster 1. The chemotaxis but inactivation of innate immunity (also leading to failure of adaptive immunity) and low tumor antigen burden resulted in immune escape of cluster 2. High expression of immune checkpoint molecules contributed to immune escape of cluster 3. In addition, we found that tumor infiltrating lymphocytes (TILs) were positively correlated with immune checkpoint molecules expression, while mutation load was negatively correlated with those indicators in triple-negative breast cancer. Analysis of enrichment pathways, mutations and somatic copy number variations between the “cold tumor” and “hot tumor” clusters revealed that amplification of MYC and activation of MYC-related pathways might decrease the immune infiltration of cluster 1. Mutations in PI3K-AKT pathway members and activation of fibroblasts-related pathways might decrease the immune infiltration of cluster 2. Conclusion Utilizing the largest single-center TNBC cohort with multi-omics data, our study first revealed the heterogeneity of the TNBC microenvironment, with translational significance both clinically and biologically. First, we identified a subtype of “hot tumor” in TNBC (cluster 3), for which immune checkpoint blockers (ICBs) might be effective. TILs and immune checkpoint molecules expression but not mutation load might predict the efficacy of ICBs. Second, we presumed some genomic alterations that might drive “cold tumor” formation in TNBC. Our study represents a step toward personalized immunotherapy for TNBC patients. Key Words triple-negative breast cancer, multi-omics, microenvironment heterogeneity, immune escape Citation Format: Xiao Y, Ma D, Zhao S, Jiang Y-Z, Shao Z-M. Microenvironment heterogeneity of triple-negative breast cancer reveals distinct immune escape mechanisms and potential driver events [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 P4-06-24.

Background: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. Emerging evidence has indicated that the extent of genetic heterogeneity may serve as a clinically useful biomarker. While several studies have suggested the prognostic value of ITH in several cancer types, the clinical significance of genetic ITH and molecular portraits that correlated with different ITH levels were poorly understood in breast cancer. The establishment of algorithms estimating genetic ITH based on sequencing of bulk tumor DNA offered us an opportunity to explore the clinical implication of ITH in large breast cancer cohorts and, for the first time, to use integrative genomic analyses to reveal molecular portraits related to intra-tumor genetic heterogeneity. Methods: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. Mutant-allele tumor heterogeneity (MATH) values were calculated from whole-exome sequencing data. We used integers nearest to the tertiles of the MATH values as cutoff points to divide the patients into three groups nearly equal in size. The association between MATH value and clinical characteristics was evaluated, followed by survival analyses in these different MATH groups. We then compared the rates of total non-silent somatic mutations among the different MATH groups, and further determined the mutations independently associated with high MATH by logistic regression adjusting for T classification and clinical subtypes. Similar methods, superadding somatic copy number alteration (SCNA) burden in logistic model, were used to evaluate SCNA events that were significantly associated with high MATH level. Gene enrichment between the high and rest MATH groups was analyzed using Gene Set Enrichment Analysis. Results: The patients were divided into low (MATH value lower than 33), intermediate (MATH between 33 and 46) and high (MATH higher than 46) MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P Conclusion: Our study extended the knowledge concerning the clinical role of ITH in breast cancer, especially the distinct pattern of prognostic values in different clinical subtypes, which may help promote the clinical utilization of genetic ITH. Our attempt at exploring the molecular features related to ITH might provide clues for the source and consequences of ITH, inspiring subsequent experiments investigating the laws underling tumor heterogeneity. Citation Format: Ma D, Jiang Y-Z, Liu X-Y, Liu Y-R, Yu K-D, Shao Z-M. Clinical and molecular relevance of intra-tumor genetic heterogeneity in breast cancer: Integrative analysis of data from The Cancer Genome Atlas [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-06-07.

Purpose: To evaluate the prognostic value of the lymph node ratio (LNR) in patients with axillary lymph node-positive triple-negative breast cancer (TNBC). Patients and methods: Based on X-tile plots, we classified women into low-, medium-, and high-risk LNR groups. Univariate and multivariate Cox proportional hazards regression analyses for overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS) were performed. The prognostic efficacy of the LNR was investigated in the first cohort from the Surveillance, Epidemiology, and End Results (SEER) database (n=4114) and was further validated in an independent cohort from Fudan University Shanghai Cancer Center (n=417). Results: The patients were classified into low- (≤0.30), medium- (0.30 to 0.70) and high-risk (>0.70) LNR groups. Multivariate analysis revealed that the LNR was an independent predictor of OS (hazard ratio (HR) for high-risk LNR: 3.24; 95% confidence interval (CI): 2.56 to 4.09) and BCSS (HR for high-risk LNR: 3.57; 95% CI: 2.76 to 4.62) in the SEER population and also for DFS (HR for high-risk LNR: 4.29; 95% CI: 2.24-8.21) in the validation population. Subgroup analysis revealed that patient classification according to the LNR could discriminate among groups of patients with different survival rates based on pN staging. Effect of Lymph Node Ratio and pN Classification on Survival Among Patients from SEERVariableOSBCSS HR a(95% CI)PHR a(95% CI)PLymph node ratio Low,≤0.301-1-Medium, >0.30 and ≤0.702.05(1.63-2.59)0.703.24(2.56-4.09) Conclusion: The LNR shows potential for use as an additional prognostic factor for TNBC patients with positive lymph node involvement. Considering the heterogeneity of TNBC, use of the LNR might allow for optimization of the pN staging system, and this ratio should be considered when making treatment decisions. Citation Format: He M, Jiang Y-Z, Tang L-C, Chen Y-L, Shao Z-M, Di G-H. The lymph node ratio as an independent prognostic factor for node-positive triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-15.

This abstract was not presented at the symposium.

We investigate the clinical characteristics, prognosis and treatment of relapsed and refractory Hodgkin's lymphoma. Twenty patients with relapsed and refractory Hodgkin lymphoma were treated by chemotherapy or autologous stem cell transplantation in our hospital from April 2006 to August 2012. The retrospective analysis of the records from the 20 patients reflected both 5-year overall survival (OS) and progression-free survival (PFS). The overall effectiveness was 80% for the 20 patients. The 5-year overall survival rate and 5-year progression-free survival rate were 73.5% and 62.7%, respectively. Therefore, comprehensive treatment should be actively utilized in the case of invalid second-line regimen for the refractory HL patients.

Purpose: The aim of this study is to evaluate the role of postmastectomy radiotherapy (PMRT) in clinical stage II and III breast cancer patients who achieved negative node status (pN0) after neoadjuvant chemotherapy (NAC). Material and methods: We retrospectively analyzed the outcomes of 143 patients with pN0 after NAC and mastectomy at Fudan University Shanghai Cancer Center. In total, 103 (72%) patients received PMRT, and 40 (28%) patients did not. Univariate and multivariate survival analyses were performed to evaluate the effect of PMRT on locoregional recurrence-free survival (LRRFS) and overall survival (OS) of the two groups. Results: There were no differences between the two groups with respect to age, nuclear grade, estrogen receptor (ER) status, HER2/neu receptor status, lymphovascular space invasion (LVSI) status or pathological tumor size. However, a significantly higher proportion of patients in the irradiated group (64%) had clinical lymph node involvement than in the nonirradiated group (45%). After a median follow-up time of 49 months, 10 locoregional recurrence events occurred. For the entire cohort of patients, use of radiation therapy improved the 5-year LRRFS rate (94.5% vs. 80.2%; P =0.032) but not the 5-year OS rate (92.2% vs. 88.7%; P =0.617). In the subset of patients who presented with clinically stage II disease, the 5-year LRRFS and 5-year OS did not differ significantly between the PMRT and no-PMRT group (96.3% vs. 91.3%; P = 0.190 and 96.2% vs. 91.3%; P = 0.199, respectively). For patients with stage III disease at diagnosis, a trend was seen toward better local regional control with PMRT (the 5-year LRRFS rate was 92.7% vs. 64.2%; P = 0.063), although the benefit from radiation with respect to OS was not significant (5-year OS rate was 88.1% vs. 85.2%; P = 0.657). On multivariate Cox regression analyses, the clinical tumor size (hazard ratio [HR], 3.27; 95% confidence interval [CI], 1.05-10.18; P = 0.041), pathologic breast tumor response (HR, 1.82; 95% CI, 1,11-3.77; P = 0.046) and delivery of radiation therapy (HR, 1.27; 95% CI, 1.08-9.25; P = 0.047) were independent predictors of locoregional recurrence. Conclusions: For patients who achieved pN0 after NAC, PMRT seemed to provide a clinical benefit for breast cancer patients with stage III disease. Omission of PMRT in patients with stage II disease did not increase the risk of locoregional recurrence and death. Citation Format: He M, Li J, Ni X-J, Chen S, Jiang Y-Z, Di G-H, Shao Z-M. Postmastectomy radiotherapy improves the outcomes of stage III breast cancer patients with negative lymph nodes after neoadjuvant chemotherapy. [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 P1-14-18.

Purpose Luminal breast cancer (estrogen receptor [ER] and/or progesterone receptor [PR] positive) represents approximately two-thirds of all breast cancer. This type of cancer constitutes a group of highly heterogeneous diseases with a sustained high risk of late recurrence. In this study, we aimed to develop comprehensive and practical nomograms for the first time to better estimate the long-term survival of luminal breast cancer. Thus, those patients with high risk of late recurrence and poor prognosis could be screened out and individualized treatments can be applied. Methods Patients with luminal breast cancer diagnosed between 1990 and 2006 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database, and randomly divided into the training (n=87,867) and validation (n=88,215) cohorts. The inclusion criteria we used to identify eligible patients were as follows: female; aged 18 to 79 years old at diagnosis; known time of diagnosis from January 1, 1990, to December 31, 2006; unilateral breast cancer; breast cancer as the first and only cancer diagnosis; diagnosis not obtained from a death certificate or autopsy; surgical treatment with either mastectomy or breast-conserving surgery; pathologic confirmation of invasive carcinoma; AJCC stages I-III; histological grade I-III and known ER and PR statuses. Patients with inflammatory breast cancer or Paget's disease and lack of data on the above inclusion criteria were also excluded. Univariate and multivariate survival analyses were applied to identify prognostic factors for overall survival (OS). The cumulative incidence function (CIF) and a competing-risks model were used to estimate the probability of breast cancer-specific survival (BCSS) and death from other causes. We integrated significant prognostic factors to build nomograms, and subjected the nomograms to bootstrap internal validation and external validation. Results We screened 176,082 luminal breast cancer cases. The mean age at diagnosis was 57.5 years, and mean survival time was 107.4 months. By the end of the last follow-up, 36,911 (21.0%) patients had died, including 17,855 (10.1%) died from breast cancer and 19,056 (10.8%) from other causes. The 5- and 10-year probabilities of overall death were 0.089 and 0.202, respectively. The 5- and 10-year probabilities of breast cancer specific-mortality (BCSM) were 0.053 and 0.112, respectively. Independent prognostic factors for both OS and BCSS were integrated to construct the nomograms, including age at diagnosis, race, tumor size, histology, grade, positive lymph nodes, ER/PR status and radiation. The calibration curves for the probabilities of 5- and 10-year OS and BCSS showed excellent agreement between the nomogram prediction and actual observation. The C-indexes of the nomograms were high in both internal validation (0.732 for OS and 0.800 for BCSS) and external validation (0.731 for OS and 0.794 for BCSS). Conclusion We established and validated nomograms that accurately predict OS and BCSS of luminal breast cancer based on a large, population-based cohort with long-term follow-up. The nomograms can identify patients with higher risk of late overall mortality and BCSM, helping physicians in facilitating individualized treatment. Citation Format: Sun W, Jiang Y-Z, Liu Y-R, Ma D, Shao Z-M. Nomograms to estimate long-term overall survival and breast cancer-specific survival of patients with luminal 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 P2-07-03.

N^(6)-methyladenosine (m^(6)A) has been identified as a conserved epitranscriptomic modification of eukaryotic mRNAs, and plays important biological roles in the regulation of cellular metabolic processes. However, its role in myogenic differentiation is unclear. Here, we altered the m^(6)A RNA methylation level by overexpression of METTL3, and explored the effect of m^(6)A RNA methylation on myogenic differentiation of murine myoblasts in vitro. The m6A RNA methylation level is regulated by exogenous methylation inhibitor cycloleucine (Cyc) and methyl donor betaine (Bet). Therefore, chemical reagents of Cyc and Bet were used to test the regulatory effect of m^(6)A RNA methylation on myogenic differentiation. Results showed that METTL3 and Bet positively regulated the m^(6)A RNA methylation levels, and Cyc negatively regulated m^(6)A RNA methylation levels. In addition, m^(6)A methylation positively regulated myogenic differentiation in murine myoblasts. These findings provide insight in the mechanisms underlying the effect of m^(6)A RNA methylation on myogenesis.

Soluble human leukocyte antigen G (sHLA-G) plays a key role in pregnancy through interaction with decidual natural killer (dNK) cell inhibitory receptors at the maternal-fetal interface. To demonstrate the possible role of sHLA-G during the pregnancy with Toxoplasma gondii infection, we compared the concentration of a murine functional homolog of sHLA-G, Qa-2, in T. gondii infected and non-infected pregnant C57BL/6 mice, and that of sHLA-G in BeWo culture supernatant. In addition, the levels of KIR2DL4 expressed on human dNK cells and NKG2A in pregnant mice were evaluated. We showed that T. gondii infection result in significant increase in the level of Qa-2 and NKG2A in pregnant mice. sHLA-G and KIR2DL4 in human samples were also significantly upregulated under the condition of T. gondii infection. The further treatment with sHLA-G antibody could reduce the expression level of KIR2DL4 which was upregulated by T. gondii infection. In summary, sHLA-G could upregulate the expression level of KIR2DL4 which lead to excessive immunological tolerance, and further contributed to T. gondii immunity escaping and affecting fetus via vertical transmission which may lead to adverse outcomes.

In order to investigate the rheological properties of altered-rock in Xiaowan Hydropower Project, triaxial creep tests were carried out on altered-rock specimens using a rock rheology testing machine. The rheological test results show that the time-dependent rheological properties of altered-rock are very significant. Based on the triaxial rheological test results, the relationship between axial strain and time under different confining pressures is investigated. The rheological effect on the stress–strain curve of altered-rock is discussed. Moreover, the relationship between axial strain rates and deviatoric stress under different stress levels is discussed in detail. The rheological failure mechanism under different confining pressures is also analysed. The triaxial rheological law of altered-rock specimen is achieved. The Burgers rheological model is used to fit the creep curves, and its parameters are obtained. The result shows that Burgers model can exactly describe the rheological properties...

MiR-222-3р has been implicated in tumor cell proliferation and has an important role in the differentiation and maturation of myogenic cells. However, its role in skeletal myoblast proliferation is still unclear. In this study, we found that miR-222-3р expression increases initially and then decreases during C2C12 myoblast proliferation. Using synthetic miRNA mimics and inhibitors in gain- or loss-of-function experiments, we snowed that miR-222-3р overexpression in C2C12 cells promotes myoblast proliferation and represses myofiber formation, while miR-222-3р downregulation has the opposite effect. Using a prediction program, BTG2 was identified as a possible target gene of miR-222-3р. During myogenesis, miR-222-3р mimics repress BTG2 expression, while miR-222-3р inhibitors promote BTG2 expression. Using dual-luciferase reporter assay, we further demonstrated that miR-222-3р specifically targets BTG2. Additionally, we show that siRNA-mediated downregulation of BTG2 expression in C2C12 myoblasts promotes the proliferation and suppresses differentiation. In conclusion, we provide a novel insight into the mechanism by which miR-222-3р regulates the proliferation and differentiation of C2C12 myoblasts by targeting BTG2. This information contributes to our understanding of the role of miRNAs in skeletal muscle development.

In order to minimise transverse wall thickness variation of seamless steel tube produced by stretch reduction, an explicit coupled thermomechanical FE model was established to simulate the stretch reduction process and corresponding experiments were carried out to validate the accuracy of the model. In addition, the plastic flow behaviour of metal in both radial and circumferential directions during forming process was analysed, and the influence of temperature on plastic flow behavior is investigated. Analysis results show that: first, the circumferential flow direction of metal is from roll groove root to roll gap in single pass rolling. Circumferential flowability of metal near the ±30° position of the roll groove shape angle is the most active, and the circumferential flowability of metal near groove root and gap is much weaker. Second, in the entire stretch reduction process, metal flows from positions of roll groove root and gap to the ±30° position of roll groove angle along the circumferen...

As the rapid development of the power industry, the analysis and forecasting of large power companies in the power market is very important. It not only makes the distribution and operation of power more reasonable, but also greatly enhances the rationality of customer power consumption. Predictive analysis with power customers is critical. Based on the service side, the electricity consumption of enterprises in Guangdong Province was selected as the training sample, and the BP neural network-based prediction algorithm was selected to study and construct the enterprise electricity package model. The effective data of 695 enterprise electricity consumption was used for training and verification. Achieve accurate package design for enterprises with different power consumption.

Background: In developed countries, T1 stage breast cancers have become the most frequently diagnosed invasive breast diseases. Patients with early stage breast cancer with lymph nodes metastasis have been proven to have more aggressive biologically phenotypes. The risk of missing metastases using sentinel lymph node biopsy can range from 1% to 4%, with a false negative rate of 10%. This evidence implies that SLNB might not be sufficient for the diagnosis of lymph node metastasis in T1 breast cancer patients. The aim of this study was to build a nomogram to predict lymph node metastasis in patients with T1 breast cancer. Methods: We identified female patients with T1 breast cancer diagnosed between 2010 and 2014 in the Surveillance, Epidemiology and End Results database. The patients were randomized into training and validation sets. Univariate and multivariate logistic regressions were carried out to assess the relationships between lymph node metastasis and age, race, and tumour size, primary site, pathological grade, histologic type, and molecular subtype. A nomogram was developed in the training set and validated by a calibration curve with the bootstrapping method and receptor operating characteristic curve analysis. Result: A total of 91,364 T1 breast cancer patients were included in the present study. For patients with T1 breast cancer, age, race, tumour size, tumour primary site, pathological grade, oestrogen receptor status, progesterone receptor status and human epidermal growth factor receptor 2 status were independent predictive factors of positive lymph node metastasis (P182). We found a significant difference in the probability of lymph node metastasis between the high and low score groups in univariate analysis in both the training set (OR=4.15, 95% CI:3.77-4.57, P Conclusions: A better understanding of the clinicopathological characteristics of T1 breast cancer patients could be vital for the assessment of their metastatic lymph node status. The nomogram developed here, if further validated in other large T1 patient cohorts, might provide additional information regarding lymph node metastasis. Together with sentinel lymph node biopsy, this nomogram can help comprehensively predict lymph node metastasis. Citation Format: Zhao Y-X, Liu Y-R, Jiang Y-Z, Xie S, Shao Z-M. A nomogram predicting lymph node metastasis in T1 breast cancer based on the surveillance, epidemiology, and end results program [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 P3-03-09.

Purpose A membrane-bound microtubule-associated protein chain 3B(LC3B) is known as one of the most specific biomarker for autophagy. The goal of this study is to investigate the prognostic value of autophagy marker LC3B in patients with residual tumors after neoadjuvant chemotherapy(NCT) for local advanced breast cancer(LABC) Patients and Methods Expression of LC3B in residual breast cancer cells were assessed by immunohistochemistry in surgical specimens from 229 patients who were diagnosed with histological proven invasive breast cancer. All patients had undergone neoadjuvant chemotherapy followed by mastectomy, and were considered as non pathological complete responders(non-pCR)after pathological evaluation. The density of positive staining of LC3B was measured with the use of a computerized image system. Prognostic value of various clinicopathologic factors was combined and evaluated by using Cox regression model. Results LC3B density was similar in the peripheral and central area of tumor(P = 0.328), however, it was siginifcantly lower in the extratumoral area(P Conclusion LC3B is a prognostic marker in non-pCR patient after neoadjuvant chemotherapy for breast cancer, which highlighting the importance of autophagy in the biological behavior of chemo-resistence cancer cells. Evaluating and targeting autophagy in neoadjuvant setting may help in prevention of disease relapse in non-pCR patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-06.

Background Girdin is identified as a novel modulator of the PI3K-Akt signaling pathway in regulating neurons integration during neurogenesis process. Recently, several studies demonstrated that Girdin and its phosphorylation type (p-Girdin) were also involved in tumor metastasis and angiogenesis. However, the clinical implications of Girdin and p-Girdin in breast cancer remain unclear. In this study, we detected the expression pattern of p-Girdin (Ser1416) and Girdin in breast cancer to uncover the association between p-Girdin/Girdin status and clinicopathological parameters like estrogen receptor (ER), progestogen receptor (PR), and human epidermal growth factor receptor 2 (Her2), etc. Methods This study included 250 patients who were histologically confirmed as invasive ductal breast cancer and underwent mastectomy in the Department of Breast Surgery in Shanghai Cancer Center during 2001 to 2006. We performed immunohistochemistry of p-Girdin/Girdin on tissue microarrays constructed from above specimens. Results We observed that Girdin was mainly located in the cytoplasm of mammary epithelial carcinoma cells (195/248, 78.63%) while p-Girdin was mainly located in the nucleus (160/250, 64.00%). However, Girdin/p-Girdin was also weakly expressed in the nucleus/cytoplasm (77/248, 31.05% for Girdin and 193/250, 77.2% for p-Girdin). By the Chi-square test, we found that Girdin in the nucleus (GN) was positively associated with ER status (P = 0.012); Girdin in the cytoplasm (GC) was positively associated with ER (P = 0.004), PR (P = 0.028), and Her2 status (P = 0.004); p-Girdin in the cytoplasm (pGC) was positively associated with PR status (P = 0.001) and negatively associated with tumor size (P = 0.025). However, no significant association was observed between p-Girdin in the nucleus (pGN) and other parameters. Using Kaplan-Meier method, we disclosed a trend that GN indicated poor disease-free survival (DFS) in ER-positive breast cancer (P = 0.075). After adjusted for histological grade and tumor size, multivariate cox regression analysis confirmed this trend (HR = 3.051, 95% CI: 1.137-8.191, P = 0.027). Furthermore, GC was prone to associating with poor DFS, especially in stage II (P = 0.079) and grade III (P = 0.058) patients. Conclusions Our work reveals, for the first time, that the location and expression pattern of both Girdin and p-Girdin (Ser1416) in breast cancer, suggesting that p-Girdin/Girdin are associated with ER, PR and Her2 status. In addition, Girdin in the nucleus is associated with poor DFS in ER-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-05.

Background: As a critical factor, age at the time of diagnosis has a significant impact on cancer therapy and outcomes. The purpose of this study is to investigate the overall mortality (OM) and breast cancer-specific mortality (BCSM) in patients with breast cancer corresponding to age at the time of diagnosis, thus constructing an age-related pattern on breast cancer survival. Methods: We analyzed data for 396,978 women aged 20-79 from 1990 to 2008 diagnosed with breast cancer from the population-based Surveillance, Epidemiology, and End Results (SEER) program of the U.S. national cancer institute. Clinicopathological factors and outcomes were compared using a chi-square test, the Kaplan-Meier method, and Cox proportional hazards regression model. Results: In the multivariable analysis, a significant relationship was found between age at the time of diagnosis and OM (p Conclusion: Patients at very young and very old age (20-29 years old and 70-79 years old) have the poorest outcomes while prognosis improves with age towards mean level. The very young age (20-29 years old) may be regarded as a significant hazard factor for BCSM in patients with ER+PR+ breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-04.

Summary Objectives of the study were ascertaining the temporal variation of fish density and biomass as well as the changes in fish species composition in a surveyed area before and after deployment of an artificial reef. The study was initiated within an area of 0.25 km2 in response to a strong demand for fisheries enhancement and resource conservation in Xiangshan Bay, Zhejiang Province, China. This survey data was collected through a SIMRAD EY60 system and bottom trinal nets pre- and post-construction of the artificial reefs, May 2011 to September 2012 in Xiangshan Bay. The raw data were analyzed using fisheries acoustic Echoview (Myriax) software combined with bottom trinal net data. The results showed that estimated fish density, represented by a nautical area scattering coefficient (NASC) at the artificial reef increased by 14.04, 31.10, 17.35% in May, July and September 2012 after construction of the artificial reef, and that the fish biomass increased by 8.92, 29.06, and 18.09% in these three months of 2012 in contrast to 2011. The numbers of fish species varied from 7 to 9 in May, from 10 to 14 in July and from 9 to 12 in September of 2012. These temporal changes in the fishery status were considered as being mainly due to deployment of the artificial reefs in early April 2012.

To evaluate the immune activity of bone marrow mesenchymal stem cells (BMSCs), and explore the biological characteristics and capabilities of BMSCs and the potential to be differentiated into neuronal cells in vitro.The BMSCs were isolated and proliferated in vitro to generate the xenogeneic mixed lymphocyte reaction. Moreover, peripheral BMSCs (pBMSCs) were added according to different ratios, which methods were stated as follows: 1: Dulbecco's Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) + 1 μmol/L all-trans-retinoic acid (ATRA) + 20 μg/L basic fibroblast growth factor (bFGF) + 20 μg/L epidermal growth factor (EGF); 2: DMEM + 2% dimethyl sulfoxide (DMSO) + 100 μmol/L butylated hydroxyanisole (BHA). The immunofluorescence and immunohistochemical staining were finally used to evaluate the differentiation capabilities of human BMSCs (hBMSCs) induced in neuronal cells.hBMSCs inhibited the lymphocyte proliferation in the mixed lymphocyte reaction (MLR) system at a proportional inhibition rate with additional numbers of stem cells. At hour 2 after culture with method 1, the plasma of hBMSCs shrank to nuclei and perinuclear bodies and was visualized under the light microscope. At hours 3-5, most of the hBMSCs formed neuron-like cells with total cell number unchanged. Afterward, the hBMSCs turned into bipolar or multipolar shaped cells and interconnected into a large network at Day 3. With immunofluorescence and immunohistochemical staining, 60-70% of the hBMSCs showed neurospecific enolase (NSE) positive and 45-50% glial fibrillary acidic protein (GFAP) positive while the Nestin-positive cells decreased to 3.4%. However, when cultured 2 hours with method 2, the most of the hBMSCs formed bipolar or multipolar shaped cells, then died after 48 hours. 40-50% NSE and 35-40% GFAP were positively expressed. Significantly, the rate of Nestin-positive cells decreased from 63% to 1.6% from hour 2 after culture to hour 48.hBMSCs may be effective for cell therapy and tissue engineering for the capability of differentiating into neuronal-like cells, as well as the capability of inhibiting lymphocyte proliferation in MLR system.

In this study, we analyzed features of 256-slice spiral CT bronchial artery imaging in common pathological types of central-type lung cancer to provide a reference for clinical diagnosis.74 patients diagnosed as central-type lung cancer were selected. They included 34 cases of squamous carcinoma and 40 cases of non-squamous carcinoma. 256-slice spiral CT bronchial artery imaging examination was performed for patients in the two groups. The 3D reconstruction technique was used in a stand-alone workstation, using different rotation axis to observe space anatomical details of the bronchial artery and to compare development ratio of the bronchial artery, artery diameter, diameter of tumor and developing condition of the pulmonary artery.It was found that left side, right side and both sides developing ratios of a bronchial artery in the squamous carcinoma group were higher than the other group. Moreover, the average diameter of the artery and diameter of the tumor was significantly higher than non-squamous carcinoma group. The occurrence rates of compression and narrowing on the pulmonary arterial branch at tumor side were significantly increased (p0.05).There were different 256-slice spiral CT bronchial artery imaging results for different pathological types of central-type lung cancer, which has a certain reference value for clinical diagnosis.

Gastric cancer (GC) is one of the most common malignant tumors worldwide, particularly, prevalent in China. Despite the decreasing incidence of GC in China, the 5-year survival rate is still not over 30% yet. Therefore, early diagnosis and therapeutic outcome evaluation of GC remains as the issue to be resolved in a clinical setting.Recent studies have found the presence of a certain amount of circulating DNA in the peripheral blood of patients with malignant tumor and shown that these free DNA bear tumor-specific genetic information. The circulating DNA detection includes quantitative and qualitative methods and analysis. Combined monitoring of changes in circulating DNA levels and aberrant alteration of relevant tumor genes is likely to provide comprehensive real-time information to patients.Under normal conditions, oncogene presents in the form of proto-oncogene such as K-ras, which is in non-carcinogenic status under the influence of tumor suppressor gene. When tumor suppressor gene is damaged or mutated of oncogene itself is induced for instance P53, oncogene is then activated and induces tumorigenesis. However, compared to gene mutation detection, the detection of DNA methylation is relatively more well-developed and stable.This article reviews the current status of the research on circulating DNA in the diagnosis, assessment of response to therapy and prognostic evaluation in GC. In addition, the advantage, current issue and prospect of using circulating DNA as tumor marker are also analyzed.

Precision medicine is an emerging medical strategy that takes into account individual molecular variations of disease to guide accurate prevention and treatment.Tumor molecular markers closely related to aggressive behavior and treatment response will be identified by integrating clinical information and multiple-omics, and will be verified in well-designed clinical trials. Breast cancer is a highly heterogeneous disease. Its treatment based on molecular subtyping has achieved initial success. However, drug resistance and tumor heterogeneity are still major challenges. This review will focus on the recent progress and future prospects of clinical research on breast cancer in the era of precision medicine.

HLA-B*40:01:47 differs from HLA-B*40:01:01 by one nucleotide exchange at position 420 in exon 3.