Metastasis-free Survival Time Research Articles

T-Lymphocyte Gene-Regulated CCL5 and Its Association with Extrahepatic Metastasis in Hepatocellular Carcinoma.

Extrahepatic metastasis in hepatocellular carcinoma (HCC) greatly limits the prognostic survival of HCC patients. Levels of preoperative peripheral lymphocyte subsets and cytokines in the serum for predicting extrahepatic spread of hepatocellular carcinoma are still not common in clinical practice. The aim of this study is to investigate the value and mechanisms of peripheral lymphocyte subsets and cytokines in predicting extrahepatic spread of HCC. We used a retrospective design to analyze data pertaining to a total of 380 patients with HCC who were examined for peripheral T-lymphocyte subsets before receiving microwave ablation. We performed Cox regression analysis to screen out independent risk factors and used pathology specimens from the patients and public databases of liver cancer to investigate the correlation between cytokines and intra-tumor immune cells. The CD4low group had better metastasis-free 1-year, 3-year, and 5-year survival rates compared to the CD4high group (80% vs 69%, 67% vs 51%, and 57% vs 39%, respectively; HR 1.7 (1.2, 2.3), P = 0.0019). Similarly, the CD8high group had better metastasis-free 1-year, 3-year, and 5-year survival rates compared to the CD8low group (65% vs 78%, 46% vs 64%, and 34% vs 54%, respectively; HR 0.6 (0.4, 0.8), P < 0.001). Patients with the CD4high/CD8low phenotype had significantly worse metastasis-free survival times compared to other patients (HR 2.0 (1.5, 2.8), P < 0.001). Additionally, T lymphocyte-specific genes (CD4, CD8) were correlated with CCL5 expression, which was also positively correlated with the level of intra-tumoral infiltrating CD8 T cells and the prognosis of HCC patients. Both CD4+ and CD8+ T lymphocyte subsets were independent risk factors for extrahepatic metastasis in HCC. Serum CCL5 levels could indicate the infiltration level of intra-tumoral CD8+ T cells and the risk of extrahepatic metastasis in HCC patients, aiding in patient risk stratification for metastasis.

Oncologic Outcomes and Predictors in Patients with Stage PT3aNxM0 Renal Cell Carcinoma Following Radical Nephrectomy.

The objective of this study is to evaluate oncologic outcomes in patients with PT3aNxM0 renal cell carcinoma following radical nephrectomy and also to investigate these outcomes in each specific subgroup of PT3a renal cell carcinoma and to determine predictive factors of recurrence, metastasis, and mortality. In this retrospective cohort study, we included 94 patients with stage PT3a renal cell carcinoma who had undergone radical nephrectomy from 2011 to 2016. All patients who had survived had at least 60 months of follow-up. Demographic and clinical data were collected; univariable and multivariable Cox proportional hazards regression analysis was performed to identify predictors of metastasis, recurrence, and cancer-related mortality. Patients' mean age was 58.07 ± 11.17 years and 62/94 (65.9%) were male. The mean follow-up time was 48.1 ± 25.5 months. Forty-three patients (45.7%) had experienced cancer-related mortality. The mean cancer-specific survival time was 60.94 months and the mean metastasis-free and local recurrence-free survival times were 57.06 and 88.72 months, respectively. Metastasis and local recurrence had occurred in 42 (44.6%) and 4 (4.25%) patients, respectively. After performing multivariate analysis, higher nuclear Fuhrman's grade (P < .001) and simultaneous involvement of the renal vein and perinephric fat (P < .001) were found to be predictive of cancerrelated mortality. Advanced nuclear Fuhrman's grade was the only independent predictor of metastasis (P=.001). Based on our results, advanced nuclear Fuhrman's grade and sarcomatoid change can independently predict mortality in patients with stage PT3aNxM0 renal cell carcinoma. Close monitoring during the follow-up period is recommended in patients with the mentioned risk factors.

LINC01376 promotes nasopharyngeal carcinoma tumorigenesis by competitively binding to the SP1/miR-4757/IGF1 axis.

The long non-coding RNA (lncRNA)-microRNA (miRNA) interaction network plays a crucial part in the pathogenesis of nasopharyngeal carcinoma (NPC). Here, we discovered a relationship between LINC01376 and miR-4757 in NPC tumor development. First, LINC01376 was abnormally overexpressed in NPC tissues and cells, and its elevated expression was associated with advanced clinicalstage and shorter distant metastasis-free survival time. Moreover, biological experiments showed that LINC01376 facilitated the proliferative, invasive, and migratory abilities of NPC cells in vitro and in vivo. Mechanistically, bioinformatics and RT-qPCR assays revealed that LINC01376 knockdown upregulated the expression level of downstream miR-4757, including miR-4757 primary transcript (pri-miR-4757) and mature miR-4757. Furthermore, LINC01376 competitively sponged the transcription factor SP1 and reduced its enrichment in the upstream promoter region of miR-4757 to repress miR-4757 expression. Finally, insulin-like growth factor 1(IGF1) was identified as the target of miR-4757. Rescue experiments indicated that LINC01376 accelerated NPC cell proliferation, migration, and invasion through the miR-4757-5p/IGF1 axis. In conclusion, the SP1/miR-4757/IGF1 axis, which is regulated by LINC01376 in NPC deterioration and metastasis, is expected to provide new insights into the molecular mechanism of NPC carcinogenesis.

PHGDH heterogeneity potentiates cancercell dissemination and metastasis.

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlow cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow cancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness.

A Novel Four Genes of Prognostic Signature for Uveal Melanoma.

Autophagy and immunity play critical roles in various cancers, but the prognostic impact of autophagy and immunity for uveal melanoma (UM) remains lacking. Therefore, the RNA sequencing of data in the TCGA-UVM dataset was downloaded from UCSC Xena database. The prognostic autophagy- and immunity-related genes (AIRGs) were selected via univariate Cox regression. Next, we applied LASSO method to construct four genes of signature in the TCGA-UVM and verified in another two GEO datasets (GSE84976 and GSE22138). This signature intimately associated with overall survival (OS) time and metastasis-free survival (MFS) time of UM, which could be considered as a prognostic indicator. Besides, by applying risk assessment, the patients of UM can be divided into two subgroups (high/low risk) with different survival time, distinct clinical outcomes, and immune microenvironments. Gene set enrichment analysis (GSEA) manifested that cancer hallmark epithelial-mesenchymal transition and KRAS pathways were positively activated in the high-risk group. Moreover, the high-risk group could be more sensitive to chemotherapies than the low-risk group. Thus, our finding suggested that the four genes of signature closely linked with UM risk and survival can afford more accurate survival prediction and potential therapeutic targets for clinical application.

HBV Infection Status Does Not Influence the Initial Metastatic Pattern and the Prognosis of Breast Cancer Patients with de novo and Relapsed Metastatic Disease.

PurposeThis study aimed to evaluate the influence of hepatitis B virus (HBV) infection status on the initial metastatic pattern and prognosis in metastatic breast cancer (MBC).MethodsMBC patients admitted to Chongqing University Cancer Hospital between January 2011 and December 2019 were enrolled. The association of HBV infection status with clinicopathological features was analyzed. The impact of HBV infection status on initial metastatic pattern and survival was evaluated.ResultsA total of 1124 patients with MBC, including 310 with de novo (cohort A) and 814 with relapsed metastatic disease (cohort B), were eligible for this study. Seropositive HBsAg was identified in 28 (9.0%) and 68 (8.4%) patients in cohort A and B, respectively. The clinicopathological features are similar between HBsAg-positive and HBsAg-negative patients. There was no significant association of HBV infection status with the rate of metastasis at each site in de novo and relapsed MBC. HBsAg-positive patients tended to have longer metastasis-free survival (MFS) and/or overall survival (OS) time, but it was not the independent prognostic factor.ConclusionIn conclusion, HBV infection status does not influence the initial metastatic pattern and the prognosis of MBC patients.

Clinical Impact of 11q13.3 Amplification on Immune Cell Infiltration and Prognosis in Breast Cancer.

IntroductionAmplification of the 11q13.3 locus has been observed in various tumors. This study sought to determine the correlation of gene amplification at the 11q13.3 locus with the immune status and survival of breast cancer.MethodsAmplification of the 11q13.3 locus was characterized by analyzing a publicly available database from the cBioPortal platform (TCGA). The correlation of amplified genes with immune cell infiltration in breast cancer was further analyzed using the TIMER2.0 platform. Immunohistochemical staining was used to determine the expression levels of Cyclin D1 (CCND1), Fas-associated death domain (FADD) and P53 in 156 clinical breast cancer samples.ResultsThis study revealed that amplification of the 11q13.3 amplicon in breast cancer is likely more frequently detected in luminal B breast cancer. Moreover, high expression or amplification of CCND1, fibroblast growth factor 3 (FGF3), fibroblast growth factor 4 (FGF4), fibroblast growth factor 19 (FGF19) and FADD was inversely correlated with the abundance of CD4+ T cells and dendritic cell infiltration in breast cancer (P < 0.05). Data analysis also demonstrated that high expression of CCND1, FGF4 and FADD mRNA levels was closely correlated with shorter recurrence-free survival (RFS) in patients with breast cancer (P < 0.05). The results of immunohistochemical staining from clinical samples further confirmed that high expression of CCND1 and FADD was frequently detected in luminal B and high-grade breast cancer with shorter metastasis-free survival times (P < 0.05).ConclusionThis study demonstrated that coamplification of genes located on the 11q13.3 amplicon is frequently detected in luminal B subtype breast cancer and is closely associated with worse survival in patients with breast cancer. Moreover, coamplification of the CCND1-FGF locus might decrease antitumor immune activity in breast cancer, indicating that coamplification of the 11q13.3 amplicon is likely to be a key determinant of therapeutic resistance and accelerate the aggressive evolution of breast cancer.

Prognostic Value of the Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Uveal Melanoma: A Clinico-Pathological and Immunohistochemical Study on a Series of 85 Cases

Uveal melanoma (UM) is the most frequent primary ocular malignancy of adults; it exhibits an almost invariably poor prognosis with onset of liver metastases within 10–15 years after the diagnosis. Serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein with proto-oncogene functions, including stimulation of angiogenesis, cell migration and cell growth; regarding the complex regulation of tumor angiogenesis, it has been suggested that SRSF1 regulates the alternative splicing of vascular endothelial growth factor-α, promoting the formation of its pro-angiogenic isoform. The immunohistochemical expression of SRSF1 on a series of 85 primary UMs, including 39 metastasizing and 46 non-metastasizing cases, was investigated; to clarify the potential pathogenetic role of SRSF1 in this tumor and its effect on angiogenesis, we correlated our immunohistochemical findings with the clinico-pathological features, the prognostic data and blood vascular microvessel density (MVD) findings of the cases from our series. Cases with higher immunohistochemical expression of SRSF1 also had higher MVD, higher metastatic potential and shorter metastasis-free survival; conversely, cases with lower SRSF1 immunoexpression showed lower MVD, lower metastatic risk and longer metastasis-free survival times. Our results suggested that SRSF1 has a negative prognostic role and a pro-angiogenic function in UM.

Venous Tumor Thrombus in Primary Bone Sarcomas in the Pelvis: A Clinical and Radiographic Study of 451 Cases.

Few investigations of venous tumor thrombus (VTT) in primary pelvic bone sarcomas are available. We aimed to identify the prevalence, associated factors, and prognosis of VTT across different types of pelvic sarcomas and to propose an algorithm for management. We included 451 consecutive cases of primary, bone-derived, treatment-naive, pelvic sarcomas in this study. Demographic data and the results of initial laboratory tests, imaging examinations, and oncological evaluations were extracted and analyzed. Forty-four cases of VTT were diagnosed with radiographic examinations, and 18 of them were verified histologically. The cohort consisted of chondrosarcomas (41.2%), osteosarcomas (30.4%), Ewing sarcomas (15.5%), bone-derived undifferentiated pleomorphic sarcomas (5.8%), and other bone sarcomas (7.1%). The prevalence of VTT was 9.8% in the whole group, and associated factors included a lactate dehydrogenase (LDH) level of ≥230.5 U/L and invasion of the L5-S1 intervertebral foramen. Patients with pelvic osteosarcoma had a high prevalence of VTT (22.6%), and the associated factors in this group included a chondroblastic subtype, an LDH level of ≥187 U/L, and invasion of the obturator foramen and the L5-S1 intervertebral foramen. Patients with VTT had a poor prognosis with a median overall survival time of 14 months. Subgroup analyses of localized pelvic osteosarcoma indicated that the presence of VTT decreased the median overall survival time (21.5 versus 54.0 months for those without VTT, p = 0.003), median recurrence-free survival time (18.6 versus 32.4 months, p = 0.020), and median metastasis-free survival time (11.2 versus 41.0 months, p < 0.001). VTT is most common in patients with pelvic osteosarcoma as compared with patients with other primary bone sarcomas, and it is associated with several factors. It is a negative prognostic factor. An algorithm for management of pelvic sarcomas with VTT stratified by the classification of the VTT might be beneficial, but further validation is necessary. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A novel signature predicts recurrence risk and therapeutic response in breast cancer patients.

Acetylserotonin O-methyltransferase (ASMT) is a key enzyme in the synthesis of melatonin. Although melatonin has been shown to exhibit anticancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles in 27 data sets on 7244 patients from 11 countries. We found that ASMT expression was significantly reduced in breast cancer tumors relative to healthy tissue. Among breast cancer patients, those with higher levels of ASMT expression had better relapse-free survival outcomes and longer metastasis-free survival times. Following treatment with tamoxifen, patients with greater ASMT expression experienced longer periods before relapse or distance recurrence. Motivated by these results, we devised an ASMT gene signature that can correctly identify low-risk cases with a sensitivity and specificity of 0.997 and 0.916, respectively. This signature was robustly validated using 23 independent breast cancer mRNA array data sets from different platforms (consisting of 5800 patients) and an RNAseq data set from TCGA (comprising 1096 patients). Intriguingly, patients who are classified as high-risk by the signature benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low-risk exhibit improved overall survival and distance relapse-free outcomes following endocrine therapy. Together, our findings more clearly elucidate the roles of ASMT, provide strategies for improving the efficacy of tamoxifen treatment and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies.

Abstract PS19-08: Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction

Abstract Second harmonic generation (SHG) is an intrinsic optical signal that can be generated from fibrillar collagen. The directionality of SHG emission is influenced by the diameter and spacing of collagen fibrils, and the disorder in their packing within collagen fibers. One measure of SHG directionality is the ratio of forward- to backward-scattered SHG, or “F/B”. F/B has been used to assess healthy vs diseased tissue in breast, ovarian, and lung cancer, and is an independent prognostic indicator of metastasis free survival time in ER+, lymph node-negative (N0), invasive ductal carcinoma (IDC). Here we assess the heterogeneity in F/B within tumor sections from ER+ N0 IDC, and its effect on the use of F/B for metastatic risk prediction. We find that F/B of tumor collagen varies between the tumor/host interface and the more cellular tumor bulk (p&amp;lt;0.0001, Student’s t-test), and that F/B from the tumor/host interface, but not tumor bulk, is prognostic of metastasis free survival in 95 IDC ER+ N0 patients (p=0.0020 and 0.10, respectively, log rank test for trend). This result was repeated with two additional image analysis procedures to generate F/B with reduced user input and hence reduced possibility of bias. Using Random Survival Forests to generate a data-driven predictive model, we find that F/B from the tumor/host interface, but not bulk, as well as a 21-gene prognostic score inferred from Affymetrix data, both contribute to predicting metastasis-free survival in this cohort. Any tool to help predict metastasis and assist with treatment decisions is likely to be applied in combination with the now well-established genomic scores. To understand how F/B can support genomic methods for guiding treatment decisions we divided our patient samples into two cohorts based upon the value of their 21-gene score relative to the TAILORx cutoff of 26 (separating low-intermediate and high-risk groups). The F/B value from tumor-host interface identifies a subgroup of patients in the low-intermediate risk group with poor clinical outcome (p=0.045, log rank test for trend). Overall, this data reveals that intratumor heterogeneity can impact the ability of F/B to predict patient outcome, and that F/B specifically from the tumor-host interface may provide a tool to better identify patients in need of adjuvant treatment or enrollment in clinical trials. Citation Format: Edward Brown, Danielle Desa, Wencheng Wu, Robert Hill, John Martens, Robert Strawderman, Bradley Turner. Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-08.

Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction

BackgroundMetastases are the leading cause of breast cancer-related deaths. The tumor microenvironment impacts cancer progression and metastatic ability. Fibrillar collagen, a major extracellular matrix component, can be studied using the light scattering phenomenon known as second-harmonic generation (SHG). The ratio of forward- to backward-scattered SHG photons (F/B) is sensitive to collagen fiber internal structure and has been shown to be an independent prognostic indicator of metastasis-free survival time (MFS). Here we assess the effects of heterogeneity in the tumor matrix on the possible use of F/B as a prognostic tool.MethodsSHG imaging was performed on sectioned primary tumor excisions from 95 untreated, estrogen receptor-positive, lymph node negative invasive ductal carcinoma patients. We identified two distinct regions whose collagen displayed different average F/B values, indicative of spatial heterogeneity: the cellular tumor bulk and surrounding tumor-stroma interface. To evaluate the impact of heterogeneity on F/B’s prognostic ability, we performed SHG imaging in the tumor bulk and tumor-stroma interface, calculated a 21-gene recurrence score (surrogate for OncotypeDX®, or S-ODX) for each patient and evaluated their combined prognostic ability.ResultsWe found that F/B measured in tumor-stroma interface, but not tumor bulk, is prognostic of MFS using three methods to select pixels for analysis: an intensity threshold selected by a blinded observer, a histogram-based thresholding method, and an adaptive thresholding method. Using both regression trees and Random Survival Forests for MFS outcome, we obtained data-driven prediction rules that show F/B from tumor-stroma interface, but not tumor bulk, and S-ODX both contribute to predicting MFS in this patient cohort. We also separated patients into low-intermediate (S-ODX < 26) and high risk (S-ODX ≥26) groups. In the low-intermediate risk group, comprised of patients not typically recommended for adjuvant chemotherapy, we find that F/B from the tumor-stroma interface is prognostic of MFS and can identify a patient cohort with poor outcomes.ConclusionsThese data demonstrate that intratumoral heterogeneity in F/B values can play an important role in its possible use as a prognostic marker, and that F/B from tumor-stroma interface of primary tumor excisions may provide useful information to stratify patients by metastatic risk.

Integrated Genome-Wide Methylation and Expression Analyses Reveal Key Regulators in Osteosarcoma.

Osteosarcoma (OS) is one of the most common types of primary bone tumors in early adolescence with unsatisfied prognosis. Aberrant DNA methylation had been demonstrated to be related to tumorigenesis and progression of multiple cancers and could serve as the potential biomarkers for the prognosis of human cancers. In conclusion, this study identified 18 downregulated hypomethylation genes and 52 upregulated hypomethylation genes in OS by integrating the analysis the GSE97529 and GSE42572 datasets. Bioinformatics analysis revealed that OS-specific methylated genes were involved in regulating multiple biological processes, including chemical synaptic transmission, transcription, response to drug, and regulating immune response. KEGG pathway analysis showed that OS-specific methylated genes were associated with the regulation of Hippo, cAMP calcium, MAPK, and Wnt signaling pathways. By analyzing R2 datasets, this study showed that the dysregulation of these OS-specific methylated genes was associated with the metastasis-free survival time in patients with OS, including CBLN4, ANKMY1, BZW1, KRTCAP3, GZMB, KRTDAP, LY9, PFKFB2, PTPN22, and CLDN7. This study provided a better understanding of the molecular mechanisms underlying the progression and OS and novel biomarkers for the prognosis of OS.

Tumour immune characterization in adenoid cystic carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures.

e15191 Background: Here, we profiled genetic hallmarks of Chinese adenoid cystic carcinoma (ACC) patients and immune cells infiltration levels by gene expression-based computational methods to investigate the correlation with immunotherapy. Methods: 54 patients with pathologically confirmed ACC admitted from January 2016 to October 2019 were included. Mutation and expression profiles were obtained by whole-exome sequencing (WES) and RNA-seq, respectively. A nomogram that integrated clinicopathological features with the immune signature to predict recurrence or distant metastasis probability was constructed by multivariate Cox regression. Results: As expected, we observed MYB fusion and somatic mutations in our cohort (57%, 31/54), strengthening the role of these aberrations as critical events in ACC. Mutations in NOTCH1 were also found in our cohort (19%, 10/54). Median tumour mutational burden (TMB) of these patients is 0.85 Muts/Mbp (0-11 Muts/Mbp). Analysis of WES data showed that all patients were microsatellite instability (MSI)-negative, and 17 of them were confirmed by conventional MSI-PCR testing. Lack of PD-L1 expression is 96.0% (n = 46/48) at a tumour proportion score 0% and 22.9% (11/48) of cases showed more than 10% CD8+ prevalence. We compared cancer types using an immune infiltration score (IIS) and an antigen presenting machinery expression (APM) score and find that ACC is among the lowest for both scores. Statistically significant correlations were found between IIS and distant metastasis-free survival (univariate analysis, HR = 2.64, 95% confidence interval [CI], 1.134 to 6.145, p = 0.023). Patients with higher IIS had shorter distant metastasis-free survival time (log-rank p = 0.020), and patients with higher T cell infiltration score (TIS) had shorter locoregional recurrence-free survival time (log-rank p = 0.050). In addition, we investigated the pretreatment immune profile of five ACC patients treated with PD-1 checkpoint inhibitors, and found that both TIS and APM were elevated in responding patient (with a partial response to camrelizumab) whereas they were in the lowest for patients with progressive disease on camrelizumab or pembrolizumab. Conclusions: Our study highlights the immune infiltration patterns and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ACC.

Expression of RARRES1 and AGBL2 and progression of conventional renal cell carcinoma

BackgroundApproximately 15% of clinically localised conventional renal cell carcinoma (RCC) will develop metastasis within 5 years of follow-up. The aim of this study was to identify biomarkers predicting the postoperative tumour relapse.MethodsTissue microarrays of conventional RCC from a cohort of 691 patients without metastasis at the time of operation were analysed by immunohistochemistry for the expression of carboxypeptase inhibitor RARRES1 and its substrate carboxypeptidase AGBL2. Univariate and multivariate Cox regression models were addressed to postoperative tumour relapse and the metastasis-free survival time was estimated by Kaplan–Meier analysis.ResultsIn multivariate analysis, the lack of staining or cytoplasmic staining of RARRES1 was a significant risk factor indicating five times higher risk of cancer relapse. Combining its co-expression with AGBL2, we found that RARRES1 cytoplasmic/negative and AGBL2-positive/negative staining is a significant risk factor for tumour progression indicating 11–15 times higher risk of cancer relapse, whereas the membranous RARRES1 expression, especially its co-expression with AGBL2, associated with excellent disease outcome.ConclusionsRARRES1 and AGBL2 expression defines groups of patients at low and high risk of tumour progression and may direct an active surveillance to detect metastasis as early as possible and to apply adjuvant therapy.

Postoperative long-term prognosis of localized renal cell carcinoma after partial or radical nephrectomy: Analysis of cancer metastasis and deaths during a more than five-year follow-up.

604 Background: We performed a long-term follow-up study to evaluate the survival and metastatic outcomes of non-metastatic renal cell carcinoma (RCC) after curative removal of tumor. Methods: We retrospectively reviewed the clinical and pathological features of 5434 patients with localized renal cell carcinoma admitted to five Korean tertiary-care institutions between 2000 and 2012, who had undergone curative surgeries with partial or radical nephrectomy with/without lymph nodal dissection. The patients below the age of 19 years (N=9) with benign histology (N=24), and with no follow-up records (N=540) were excluded. A total of 4861 patients, followed-up for at least 1 year after the surgery, were enrolled finally. The deaths were defined as intraoperative, postoperative or RCC-related deaths. We analyzed the metastasis-free survival, cancer-specific survival, and overall survival outcomes according to the pathological stages. Results: The median age of patients at the time of surgery, male-to-female ratios, median follow-up duration, overall survival and metastasis-free survival times were 56 years (range: 19-94 years), 3471/1390 (71.4%/28.6%), 33.7 months (range: 12-297 months), 175.1 months (12-297.1 months), and 61 months (range: 12-94 months), respectively. A total of 518 (10.7%) deaths, including 338 (7.0%) RCC-related death and 164 (3.3%) deaths related to other causes were reported. Metastasis and recurrences were observed in 140 (2.9%) and 462 (9.5%) patients, respectively. The respective pathologic T1/2/3/4/x and N1 stages, namely, 3757/389/644/57/6 (77.3/8.0/13.3/1.2/0.1%) and 133 (2.7%) were observed. The rates of histological types of clear cell papillary/ chromophobe/ collecting duct/ unclassified/ MLCRCCLMP/ mixed cell papillary/ unknown were 83.4%/ 1.5%/ 7.1%/ 0.4%/ 1.1%/ 0.5%/ 0.2%/ 0.3%/ 0.1%/ 5.3%. The 10-year metastasis-free survival rate was 86.0% including 100%, 91.0%, 64.1%, and 11.8% incidence for stages I, II, III, and IV, respectively. Conclusions: The long-term survival was seen among patients who underwent nephrectomy for non-metastatic renal cell carcinoma.

Use of clinical nomograms for predicting survival outcomes in young women with breast cancer.

Early-onset breast cancer (BC) has been recognized to be more aggressive compared with its later counterparts. Survival models of BC in young patients have rarely been reported in previous studies. The current study aimed to establish and validate prediction models with clinicopathological variables for visceral metastasis-free survival (VFS), disease-free-survival (DFS) and overall survival (OS) time in young patients with BC. Clinicopathological data were obtained for 351 patients with primary breast tumors who were ≤40 years old. Univariate and multivariate analyses were performed and nomograms were established to screen and illustrate the prognostic factors. Risk scores were calculated based on coefficients from the Cox regression analysis. Internal validation of the prediction models was conducted by predicting the prognosis of cases randomly sampled from the cohort used in the current study. Multivariate analysis demonstrated that N stage (P=0.004), molecular subtype (P=0.007) and age (P=0.005) were significant independent prognostic factors for VFS. Similarly, N stage (P=0.002) and molecular subtype (P=0.001) were significantly associated with DFS. In addition, N stage (P=0.006), molecular subtype (P=0.006) and the presence of an initially inoperable tumor (P=0.005) were significant independent prognostic factors for OS. According to the Cox regression analysis, nomograms were generated to illustrate the effect of independent prognostic factors on VFS, DFS and OS. Risk scores were calculated and internal validation demonstrated the reliability of the prediction models. In conclusion, N stage and molecular subtype were identified as predictors for VFS, DFS and OS in early-onset BC. Furthermore, an age of <35 years at diagnosis was revealed to be unfavorable for VFS and the presence of an initially inoperable tumor was identified to reduce OS time.

CEACAM6 is associated with osteosarcoma metastasis and facilitates epithelial-mesenchymal transition in osteosarcoma cells.

BackgroundCarcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of CEACAM family and has been reported to be upregulated in various types of human cancer and involved in tumor progression and metastasis. However, the biological roles and clinical significances of CEACAM6 in osteosarcoma still remain to be elucidated.Materials and methodsReal-timePCR, immunohistochemistry and Western blot analysis were used to determine CEACAM6 expression in osteosarcoma cell lines and clinical specimens. Then the clinical relevance of CEACAM6 was analyzed in osteosarcoma. The function of CEACAM6 in osteosarcoma was examined by wound-healing and cell invasion assays, and expression levels of epithelial–mesenchymal transition markers.ResultsIn the present study, we found that CEACAM6 was markedly upregulated in metastatic osteosarcoma tissues when compared with the nonmetastatic osteosarcoma tissues. Upregulation of CEACAM6 was significantly associated with lung metastasis status (P=0.006) in patients with osteosarcoma. Survival analyses suggested that osteosarcoma patients with high CEACAM6 expression had a significantly shorter overall survival time and lung metastasis-free survival time than those with low CEACAM6 expression. Knockdown of CEACAM6 inhibits osteosarcoma cell migration and invasion. Moreover, silencing CEACAM6 suppressed osteosarcoma cells epithelial–mesenchymal transition.ConclusionTaken together, this study suggests that CEACAM6 might be a promising biomarker and a potential therapeutic target for the treatment of metastatic osteosarcoma.

DNA damage and repair (DDR) gene variants and outcomes in localized and metastatic prostate cancer (mPC).

304 Background: Moderate frequencies of DDR gene variants exist in mPC. Their prognostic role in localized and mPC is unclear. This study aims to characterize DDR variants in a cohort of hormone sensitive localized and mPC and assess for association with outcome. Methods: A retrospective cohort of men with PC and ≥ 2 follow up visits at DFCI and targeted next generation sequencing of prostate or metastatic tissue was identified. Biomarker (BM) positive was defined as pathogenic changes in the following DDR genes: ATM BAP1 BRCA1 BRCA2 BRIP1 CHEK2 MSH2 MSH6 PALB2 PMS2. For localized PC, outcome endpoints included event-free survival (EFS) (time from prostate biopsy to PSA relapse/metastasis/death), metastasis-free survival (MFS) (time to metastasis/death), time to castration resistance (CRPC), and death (OS); for mPC, outcome events included time from androgen deprivation start to CRPC and OS. BM status was descriptively summarized. Kaplan-Meier method and Cox regression model assessed associations of BM status with clinical outcomes. Results: Of the 237 men included, 16 (7%) were BM positive; 12 (6%) in 205 localized PC, 6 (14%) in 43 mPC. BM positive genes included 9 (4%) ATM, 6 (3%) BRCA2, and 2 (0.8%) CHEK2. In men with localized PC, EFS events occurred in 58% (7/12) BM positive vs 34% (66/193) BM negative at median follow up of 3.1 years; BM positive trended toward a shorter EFS (median 1.9 vs 5 years) than BM negative (HR 2.17, 95%CI 0.99-4.76). MFS events were observed in 17% (2/12) BM positive vs 7% (15/193) BM negative. CRPC events occurred in 17% (2/12) BM positive vs 6% (11/193) BM negative. In men with mPC, there were CRPC events in 100% (6/6) BM positive vs 67% (25/37) BM negative at median follow up of 3.3 years; BM positive trended toward a shorter time to CRPC (median 4 vs 8.8 months) compared to BM negative (HR 1.87, 95%CI 0.76-4.64). There was no association between BM status and OS. Conclusions: DDR variants appear infrequently in localized PC but may portend a shorter time to PSA relapse and metastasis. Similarly, DDR variants in mPC may be associated with a shorter time to CRPC. Low frequency of variants and short follow up limit these analyses. The prognostic value of DDR variants remains unclear and requires further research.

Apalutamide for the treatment of patients with castration-resistant prostate cancer.

Patients with recurrent, nonmetastatic prostate cancer after curative intent therapy can experience a heterogeneous clinical course ranging from indolent disease that can be observed for years to a rapidly progressive disease that is metastatic in a relatively short time. Patients with short prostate-specific antigen (PSA) doubling times are at risk for early development of metastatic disease and are frequently placed on androgen deprivation therapy. Although castration-resistant disease inevitably occurs in these patients, most therapies for castration-resistant disease have shown benefit in the metastatic setting. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor, preventing androgen receptor translocation, DNA binding and androgen receptor-mediated transcription. Apalutamide showed improved metastasis-free survival and prolonged time to symptomatic progression in men with nonmetastatic castration-resistant prostate cancer with a short PSA doubling time.