Biomarker Commons

Sphingosine kinase 1 is overexpressed and promotes proliferation in human thyroid cancer.

Mol Endocrinol. 2011 Nov;25(11):1858-66

Authors: Guan H, Liu L, Cai J, Liu J, Ye C, Li M, Li Y

Abstract
Sphingosine kinase 1 (SphK1), an oncogenic kinase, has been previously found to be elevated in various types of human cancer and play a role in tumor development and progression. Nevertheless, the biological and clinical significance of SphK1 in thyroid cancer is largely unknown. Here, we demonstrate that the expression of SphK1 is generally up-regulated in thyroid cancer and that its expression level is correlated with the degree of thyroid malignancy. Silencing SphK1 by specific RNA interference is able to suppress the proliferation of thyroid cancer cells, and SphK1 expression level is strongly associated with the expression of proliferation cell nuclear antigen in thyroid cancer tissues. Of particular note is that depletion of SphK1 results in dephosphorylation of protein kinase B and glycogen synthase kinase-3β and subsequent inactivation of β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity. Hence, taken together, our study has identified SphK1 as a proproliferative oncogenic kinase, an Akt/glycogen synthase kinase-3β/β-catenin activator, and probably a biomarker for thyroid cancer as well.

PMID: 21940753 [PubMed - indexed for MEDLINE]

Enhanced discrimination of malignant from benign pancreatic disease by measuring the CA 19-9 antigen on specific protein carriers.

PLoS One. 2011;6(12):e29180

Authors: Yue T, Maupin KA, Fallon B, Li L, Partyka K, Anderson MA, Brenner DE, Kaul K, Zeh H, Moser AJ, Simeone DM, Feng Z, Brand RE, Haab BB

Abstract
The CA 19-9 assay detects a carbohydrate antigen on multiple protein carriers, some of which may be preferential carriers of the antigen in cancer. We tested the hypothesis that the measurement of the CA 19-9 antigen on individual proteins could improve performance over the standard CA 19-9 assay. We used antibody arrays to measure the levels of the CA 19-9 antigen on multiple proteins in serum or plasma samples from patients with pancreatic adenocarcinoma or pancreatitis. Sample sets from three different institutions were examined, comprising 531 individual samples. The measurement of the CA 19-9 antigen on any individual protein did not improve upon the performance of the standard CA 19-9 assay (82% sensitivity at 75% specificity for early-stage cancer), owing to diversity among patients in their CA 19-9 protein carriers. However, a subset of cancer patients with no elevation in the standard CA 19-9 assay showed elevations of the CA 19-9 antigen specifically on the proteins MUC5AC or MUC16 in all sample sets. By combining measurements of the standard CA 19-9 assay with detection of CA 19-9 on MUC5AC and MUC16, the sensitivity of cancer detection was improved relative to CA 19-9 alone in each sample set, achieving 67-80% sensitivity at 98% specificity. This finding demonstrates the value of measuring glycans on specific proteins for improving biomarker performance. Diagnostic tests with improved sensitivity for detecting pancreatic cancer could have important applications for improving the treatment and management of patients suffering from this disease.

PMID: 22220206 [PubMed - indexed for MEDLINE]

Filamin-A as a marker and target for DNA damage based cancer therapy.

DNA Repair (Amst). 2012 Feb 1;11(2):192-200

Authors: Yue J, Lu H, Liu J, Berwick M, Shen Z

Abstract
Filamin-A, also called actin binding protein 280 (ABP-280), cross-links the actin filaments into dynamic orthogonal network to serve as scaffolds in multiple signaling pathways. It has been reported that filamin-A interacts with DNA damage response proteins BRCA1 and BRCA2. Defects of filamin-A impair the repair of DNA double strand breaks (DSBs), resulting in sensitization of cells to ionizing radiation. In this study, we sought to test the hypothesis that filamin-A can be used as a target for cancer chemotherapy and as a biomarker to predict cancer response to therapeutic DNA damage. We found that reduction of filamin-A sensitizes cancer cells to chemotherapy reagents bleomycin and cisplatin, delays the repair of not only DSBs but also single strand breaks (SSBs) and interstrand crosslinks (ICLs), and increases chromosome breaks after the drug treatment. By treating a panel of human melanoma cell lines with variable filamin-A expression, we observed a correlation between expression level of filamin-A protein and drug IC(50). We further inhibited the expression of filamin-A in melanoma cells, and found that this confers an increased sensitivity to bleomycin and cisplatin treatment in a mouse xenograft tumor model. These results suggest that filamin-A plays a role in repair of a variety of DNA damage, that lack of filamin-A is a prognostic marker for a better outcome after DNA damage based treatment, and filamin-A can be inhibited to sensitize filamin-A positive cancer cells to therapeutic DNA damage. Thus filamin-A can be used as a biomarker and a target for DNA damage based cancer therapy.

PMID: 22051193 [PubMed - indexed for MEDLINE]

Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies.

Int J Cancer. 2012 Jun 1;130(11):2728-33

Authors: Ramos JC, Sin SH, Staudt MR, Roy D, Vahrson W, Dezube BJ, Harrington W, Dittmer DP

Abstract
The nuclear factor kappa B (NFκB) pathway is essential for many human cancers. Therapeutics such as bortezomib (Velcade™) that interfere with NFκB signaling are of great clinical interest. NFκB signaling, however, is multifaceted and variable among tissues, developmental and disease entities. Hence, targeted biomarkers of NFκB pathways are of prime importance for clinical research. We developed a novel real-time qPCR-based NFκB array. Only mechanistically validated NFκB targets were included. We then used random-forest classification to define individual genes and gene combinations within the NFκB pathways that define viral lymphoma subclasses as well as Kaposi sarcoma (KS). Few NFκB targets emerged that were universally present in all tumor types tested, underscoring the need for additional tumor-type specific biomarker discovery. (i) We uncovered tissue of origin-specific tumor markers, specifically CD69, CSF-1 and complement factor B (C1QBP) for primary effusion lymphoma (PEL); IL1-beta, cyclinD3 and CD48 for KS. We found that IL12, jun-B, msx-1 and thrombospondin 2 were associated with EBV co-infection in PEL. (ii) We defined the NFκB signature of Epstein-Barr virus (EBV) positive AIDS-associated Burkitt lymphoma (BL). This signature identified CCR5 as the key marker. (iii) This signature differed from EBV negative BL consistent with the idea that EBV not only activates NFκB activity but that this virus also reprograms NFκB signaling toward different targets.

PMID: 21792887 [PubMed - indexed for MEDLINE]

Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population.

Tumour Biol. 2012 Apr;33(2):395-402

Authors: Ahmad ST, Arjumand W, Seth A, Saini AK, Sultana S

Abstract
Aberrant promoter hypermethylation of cancer associated genes occur frequently during carcinogenesis and may serve as a cancer biomarker. The aim of this study was to investigate the occurrence and relevance of promoter methylation of the tumor suppressor DAPK-1, APAF-1 () and SPARC in relation to different pathological stages and histological grades of tumor progression that might act as possible independent prognostic factor in the susceptibility towards renal cell carcinoma (RCC) in North Indian population. Three tumor suppressor gene promoters namely APAF-1, DAPK-1 and SPARC were assessed by methylation-specific PCR (MS-PCR) in 196 primarily resected renal cell tumors paired with the corresponding normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters, pathological stage and Fuhrman nuclear grade of RCC. Significant differences in methylation frequency among the four subtypes of renal tumors were found for APAF-1 (p < 0.001), DAPK-1 (p < 0.001) and SPARC (p = 0.182), when compared with the corresponding normal tissue. Male subjects showed stronger association of methylation frequency of all the three genes with RCC than the female subjects. Additionally, higher frequency of APAF-1, DAPK-1 and SPARC promoter methylation were directly correlated with higher tumor stage (p (trend) < 0.001). Higher frequency of promoter methylation of APAF-1 and SPARC were also associated with higher nuclear grade (p < 0.001 and p = 0.036, respectively). This gene panel might contribute to a more optimal diagnostic coverage and information, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.

PMID: 21922274 [PubMed - indexed for MEDLINE]

Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance.

Genes Chromosomes Cancer. 2011 Dec;50(12):1043-53

Authors: Narayan G, Freddy AJ, Xie D, Liyanage H, Clark L, Kisselev S, Un Kang J, Nandula SV, McGuinn C, Subramaniyam S, Alobeid B, Satwani P, Savage D, Bhagat G, Murty VV

Abstract
PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B-cell (81.9%) and T-cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation-mediated inactivation of PCDH10 were less sensitive to commonly used leukemia-specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid-lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.

PMID: 21960365 [PubMed - indexed for MEDLINE]

Rho GDP-dissociation inhibitor alpha is associated with cancer metastasis in colon and prostate cancer.

Pharmazie. 2012 Mar;67(3):253-5

Authors: Yamashita T, Okamura T, Nagano K, Imai S, Abe Y, Nabeshi H, Yoshikawa T, Yoshioka Y, Kamada H, Tsutsumi Y, Tsunoda S

Abstract
Since metastasis is one of the most important prognostic factors in colorectal cancer, development of new methods to diagnose and prevent metastasis is highly desirable. However, the molecular mechanisms leading to the metastatic phenotype have not been well elucidated. In this study, a proteomics-based search was carried out for metastasis-related proteins in colorectal cancer by analyzing the differential expression of proteins in primary versus metastasis focus-derived colorectal tumor cells. Protein expression profiles were determined using a tissue microarray (TMA), and the results identified Rho GDP-dissociation inhibitor alpha (Rho GDI) as a metastasis-related protein in colon and prostate cancer patients. Consequently, Rho GDI may be useful as a diagnostic biomarker and/or a therapeutic to prevent colon and prostate cancer metastasis.

PMID: 22530308 [PubMed - indexed for MEDLINE]

Advancements in the use of blood tests for cancer screening in women at high risk for endometrial and breast cancer.

Future Oncol. 2011 Dec;7(12):1399-414

Authors: Ambeba E, Linkov F

Abstract
Several years ago, it was argued that the identification of serum biomarkers is one of the most promising approaches for the detection of early-stage malignant or even premalignant lesions. In this review, the need to establish better monitoring protocols is described for obese women who are at higher risk for the development of malignancies commonly associated with excess weight; specifically endometrial and postmenopausal breast cancer. These cancers have been chosen for this review article as our aim was to focus on female cancers that have been linked with obesity. Cancer screening is essential in detecting disease in its earliest stage in order to reduce morbidity and mortality; however, effective screening is not available for many cancer types. Even for cancers that have effective screening protocols available, there are barriers to screening in obese individuals, such as reduced mobility and embarrassment. These barriers often delay screening in these vulnerable population groups, leading to detection of the disease at a more advanced stage and ultimately leading to a poorer prognosis. As of today, biomarkers do not replace but augment imaging and other existing screening approaches. Future development of blood- or urine-based biomarkers as a way to screen individuals at high risk for certain cancers may prove to be an excellent method for overcoming the barriers that individuals at high risk are facing today. The overall purpose of this manuscript is to provide an overview of screening techniques and to identified barriers and alternate biomarker-based approaches for improvement of endometrial and breast cancer screening in obese women.

PMID: 22112316 [PubMed - indexed for MEDLINE]

Identifying cancer biomarkers by network-constrained support vector machines.

BMC Syst Biol. 2011;5:161

Authors: Chen L, Xuan J, Riggins RB, Clarke R, Wang Y

Abstract
BACKGROUND: One of the major goals in gene and protein expression profiling of cancer is to identify biomarkers and build classification models for prediction of disease prognosis or treatment response. Many traditional statistical methods, based on microarray gene expression data alone and individual genes' discriminatory power, often fail to identify biologically meaningful biomarkers thus resulting in poor prediction performance across data sets. Nonetheless, the variables in multivariable classifiers should synergistically interact to produce more effective classifiers than individual biomarkers.
RESULTS: We developed an integrated approach, namely network-constrained support vector machine (netSVM), for cancer biomarker identification with an improved prediction performance. The netSVM approach is specifically designed for network biomarker identification by integrating gene expression data and protein-protein interaction data. We first evaluated the effectiveness of netSVM using simulation studies, demonstrating its improved performance over state-of-the-art network-based methods and gene-based methods for network biomarker identification. We then applied the netSVM approach to two breast cancer data sets to identify prognostic signatures for prediction of breast cancer metastasis. The experimental results show that: (1) network biomarkers identified by netSVM are highly enriched in biological pathways associated with cancer progression; (2) prediction performance is much improved when tested across different data sets. Specifically, many genes related to apoptosis, cell cycle, and cell proliferation, which are hallmark signatures of breast cancer metastasis, were identified by the netSVM approach. More importantly, several novel hub genes, biologically important with many interactions in PPI network but often showing little change in expression as compared with their downstream genes, were also identified as network biomarkers; the genes were enriched in signaling pathways such as TGF-beta signaling pathway, MAPK signaling pathway, and JAK-STAT signaling pathway. These signaling pathways may provide new insight to the underlying mechanism of breast cancer metastasis.
CONCLUSIONS: We have developed a network-based approach for cancer biomarker identification, netSVM, resulting in an improved prediction performance with network biomarkers. We have applied the netSVM approach to breast cancer gene expression data to predict metastasis in patients. Network biomarkers identified by netSVM reveal potential signaling pathways associated with breast cancer metastasis, and help improve the prediction performance across independent data sets.

PMID: 21992556 [PubMed - indexed for MEDLINE]

Next-generation sequencing identifies novel microRNAs in peripheral blood of lung cancer patients.

Mol Biosyst. 2011 Dec;7(12):3187-99

Authors: Keller A, Backes C, Leidinger P, Kefer N, Boisguerin V, Barbacioru C, Vogel B, Matzas M, Huwer H, Katus HA, Stähler C, Meder B, Meese E

Abstract
MicroRNAs (miRNAs) are increasingly envisaged as biomarkers for various tumor and non-tumor diseases. MiRNA biomarker identification is, as of now, mostly performed in a candidate approach, limiting discovery to annotated miRNAs and ignoring unknown ones with potential diagnostic value. Here, we applied high-throughput SOLiD transcriptome sequencing of miRNAs expressed in human peripheral blood of patients with lung cancer. We developed a bioinformatics pipeline to generate profiles of miRNA markers and to detect novel miRNAs with diagnostic information. Applying our approach, we detected 76 previously unknown miRNAs and 41 novel mature forms of known precursors. In addition, we identified 32 annotated and seven unknown miRNAs that were significantly altered in cancer patients. These results demonstrate that deep sequencing of small RNAs bears high potential to quantify miRNAs in peripheral blood and to identify previously unknown miRNAs serving as biomarker for lung cancer.

PMID: 22027949 [PubMed - indexed for MEDLINE]

Promoter methylation of H-cadherin is a potential biomarker in patients with bladder transitional cell carcinoma.

Int Urol Nephrol. 2012 Feb;44(1):111-7

Authors: Lin YL, Liu XQ, Li WP, Sun G, Zhang CT

Abstract
OBJECTIVES: H-cadherin, functions as a tumor suppressor, is frequently silenced by promoter methylation in human cancers. The aim of this study was to evaluate the feasibility of using H-cadherin methylation in tumor tissues as a potential biomarker in patients with bladder transitional cell carcinoma (TCC).
MATERIALS AND METHODS: We examined the methylation status of H-cadherin in 133 primary bladder TCC samples and 43 normal bladder epithelial tissues using methylation-specific polymerase chain reaction (MSP) and then analyzed the associations between H-cadherin methylation and clinicopathologic features as well as patients' outcome.
RESULTS: H-cadherin methylation was detected in 47 (35.3%) bladder TCC samples, but not found in controls (P = 0.0000). Moreover, H-cadherin methylation was significantly associated with advanced stage (P = 0.0006), high grade (P = 0.0165), larger tumor size (P = 0.0225), tumor recurrence (P = 0.0106), and poor prognosis (P = 0.0000). In addition, multivariate analysis indicated that H-cadherin methylation is independently associated with poor outcome and had a relative risk of death of 3.832 (P = 0.0071, 95% confidence interval: 1.443-10.176).
CONCLUSIONS: The results suggest that H-cadherin methylation may be used as a potential biomarker for the malignancy of bladder TCC and as an independent prognostic biomarker in patients with bladder TCC.

PMID: 21516472 [PubMed - indexed for MEDLINE]

Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches.

J Thorac Oncol. 2012 Feb;7(2):306-15

Authors: Krebs MG, Hou JM, Sloane R, Lancashire L, Priest L, Nonaka D, Ward TH, Backen A, Clack G, Hughes A, Ranson M, Blackhall FH, Dive C

Abstract
INTRODUCTION: Epithelial circulating tumor cells (CTCs) are detectable in patients with non-small cell lung cancer (NSCLC). However, epithelial to mesenchymal transition, a widely reported prerequisite for metastasis, may lead to an underestimation of CTC number. We compared directly an epithelial marker-dependent (CellSearch) and a marker-independent (isolation by size of epithelial tumor cells [ISET]) technology platform for the ability to identify CTCs. Molecular characteristics of CTCs were also explored.
METHODS: Paired peripheral blood samples were collected from 40 chemonäive, stages IIIA to IV NSCLC patients. CTCs were enumerated by Epithelial Cell Adhesion Molecule-based immunomagnetic capture (CellSearch, Veridex) and by filtration (ISET, RareCell Diagnostics). CTCs isolated by filtration were assessed by immunohistochemistry for epithelial marker expression (cytokeratins, Epithelial Cell Adhesion Molecule, epidermal growth factor receptor) and for proliferation status (Ki67).
RESULTS: CTCs were detected using ISET in 32 of 40 (80%) patients compared with 9 of 40 (23%) patients using CellSearch. A subpopulation of CTCs isolated by ISET did not express epithelial markers. Circulating tumor microemboli (CTM, clusters of ≥ 3 CTCs) were observed in 43% patients using ISET but were undetectable by CellSearch. Up to 62% of single CTCs were positive for the proliferation marker Ki67, whereas cells within CTM were nonproliferative.
CONCLUSIONS: Both technology platforms detected NSCLC CTCs. ISET detected higher numbers of CTCs including epithelial marker negative tumor cells. ISET also isolated CTM and permitted molecular characterization. Combined with our previous CellSearch data confirming CTC number as an independent prognostic biomarker for NSCLC, we propose that this complementary dual technology approach to CTC analysis allows more complete exploration of CTCs in patients with NSCLC.

PMID: 22173704 [PubMed - indexed for MEDLINE]

ΔNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach.

J Thorac Oncol. 2012 Feb;7(2):281-90

Authors: Pelosi G, Fabbri A, Bianchi F, Maisonneuve P, Rossi G, Barbareschi M, Graziano P, Cavazza A, Rekhtman N, Pastorino U, Scanagatta P, Papotti M

Abstract
INTRODUCTION: Diagnosing non-small cell lung cancer on biopsy/cellblock samples by morphology may be demanding. As sparing material for molecular testing is mandatory, a minimalist immunohistochemistry (IHC)-based diagnostic approach is warranted by means of novel, reliable, and easy-to-assess biomarkers.
METHODS: Forty-six consecutive biopsy/cellblock samples and the corresponding resection specimens (as the gold standard for morphology and IHC) from 30 adenocarcinomas (AD), 10 squamous carcinomas (SQC), 5 adenosquamous carcinomas (ADSQC), and 1 sarcomatoid carcinoma (SC) were IHC-evaluated for p40 [corresponding to nontransactivating ΔNp63 isoforms] and thyroid transcription factor-1 (TTF1) by semiquantitative assessment. For p40, also immunodecoration intensity was taken into account and dichotomized as strong or low.
RESULTS: Nonrandom and overlapping distributions of the relevant markers were found in biopsy/cellblock and surgical specimens, which closely correlated with each other and the diverse tumor categories, with no differences in area under curve-receiver-operating-characteristic curves for each marker between any two samples, including p40 and p63. Diagnostic combinations were p40-/TTF1+ or TTF1- for AD (where p40 was negative, apart from 5/30 AD showing at the best 1-2% tumor cells with low intensity); p40+/TTF1- (p40 strong and by far higher than 50%) for SQC; and p40+/TTF1+ or p40+/TTF1- (p40 strong and less than 50%) for ADSQC. The single SC case was p40-/TTF1-, suggesting glandular lineage. Practically, 41/46 (89%) tumors were correctly classified by IHC on small samples, including 30 AD, 10 SQC, 1/5 ADSQC, and no SC. Underdiagnosis of ADSQC was actually because of sampling error of biopsies/cellblocks rather than insufficient biomarker robustness, whereas underdiagnosis of SC was really because of the failure of either marker to highlight epithelial-mesenchymal transition.
CONCLUSIONS: This minimalist IHC-based model of p40 and TTF1 on biopsy/cellblock samples was effective to correctly subtype most cases of lung cancer.

PMID: 22071786 [PubMed - indexed for MEDLINE]

Fast detection of choline-containing metabolites in liver using 2D ¹H-¹⁴N three-bond correlation (HN3BC) spectroscopy.

J Magn Reson. 2012 Jan;214(1):352-9

Authors: Mao XA, Li N, Mao J, Li Q, Xiao N, Jiang B, Jiang L, Wang XX, Liu M

Abstract
Detection and quantification of total choline-containing metabolites (CCMs) in tissues by magnetic resonance spectroscopy (MRS) has received considerable attention as a biomarker of cancer. Tissue CCMs are mainly choline (Cho), phosphocholine (PCho), and glycerophosphocholine (GPCho). Because the methyl (1)H resonances of tissue CCMs exhibit small chemical shift differences and overlap significantly in 1D (1)H MRS, quantification of individual components is precluded. Development of a MRS method capably of resolving individual components of tissue CCMs would be a significant advance. Herein, a modification of the 2D (1)H-(14)N HSQC technique is targeted on the two methylene (1)H in the CH(2)O group ((3)J(1H14N)=2.7 Hz) and applied to ex vivo mouse and human liver samples at physiological temperature (37°C). Specifically, the (1)H-(14)N HSQC technique is modified into a 2D (1)H-(14)N three-bond correlation (HN3BC) experiment, which selectively detects the (1)H of CH(2)O coupled to (14)N in CCMs. Separate signals from Cho, PCho, and GPCho components are resolved with high detection sensitivity. A 2D HN3BC spectrum can be recorded from mouse liver in only 1.5 min and from human carcinoma liver tissue in less than 3 min with effective sample volume of 0.2 ml at 14.1T.

PMID: 22204824 [PubMed - indexed for MEDLINE]

Interval to biochemical failure as a biomarker for cause-specific and overall survival after dose-escalated external beam radiation therapy for prostate cancer.

Cancer. 2012 Apr 15;118(8):2059-68

Authors: Kapadia NS, Olson K, Sandler HM, Feng FY, Hamstra DA

Abstract
BACKGROUND: After external beam radiation therapy (EBRT) for prostate cancer, a short interval to biochemical failure of <18 months has been proposed as a surrogate for cause-specific survival. Because EBRT dose influences biochemical failure, the authors investigated the interval to biochemical failure in a cohort of patients treated with dose-escalated EBRT.
METHODS: From 1998 to 2008, 710 patients were treated with EBRT (≥75 grays) ± androgen deprivation therapy (ADT) at the University of Michigan. Biochemical failure was defined using the Phoenix consensus definition (nadir + 2 ng/mL). A short interval to biochemical failure was defined as <18 months after completing radiotherapy and/or ADT. The associations between biochemical failure, the interval to biochemical failure, and clinical factors with cause-specific survival (CSS) and overall survival (OS) were evaluated.
RESULTS: There were 149 biochemical failures (21%), and short interval to biochemical failure accounted for 14% and 40% of biochemical failures in those with intermediate-risk or high-risk disease, respectively. Biochemical failure impacted CSS (P < .0001) but not OS (P = .36). However, a short interval to biochemical failure predicted decreased CSS (P < .0001; hazard ratio [HR], 5.6; 95% confidence interval [CI], 2.4-13.0) and OS (P < .0001; HR, 4.8; 95% CI, 2.3-10.3) when compared with a long interval to biochemical failure. The 8-year OS was 78% without biochemical failure, compared with 87% with a long interval to biochemical failure (P = .1; HR, 0.7; 95% CI, 0.4-1.1) and 38% with a short interval to biochemical failure (P < .0001; HR, 3.7; 95% CI, 2.3-5.9). On multivariate analysis, a short interval to biochemical failure increased the risk of prostate cancer death (P < .0001; HR, 18.1; 95% CI, 8.4-39) and all cause mortality (P = .0027; HR, 1.5; 95% CI, 1.2-2.1), whereas a long interval to biochemical failure did not.
CONCLUSIONS: The relation between the interval to biochemical failure, CSS, and OS was independently validated in patients treated with dose-escalated EBRT. Further evaluation of the interval to biochemical failure as a surrogate endpoint is warranted.

PMID: 22009287 [PubMed - indexed for MEDLINE]

Rho GDP-dissociation inhibitor alpha is associated with cancer metastasis in colon and prostate cancer.

Pharmazie. 2012 Mar;67(3):253-5

Authors: Yamashita T, Okamura T, Nagano K, Imai S, Abe Y, Nabeshi H, Yoshikawa T, Yoshioka Y, Kamada H, Tsutsumi Y, Tsunoda S

Abstract
Since metastasis is one of the most important prognostic factors in colorectal cancer, development of new methods to diagnose and prevent metastasis is highly desirable. However, the molecular mechanisms leading to the metastatic phenotype have not been well elucidated. In this study, a proteomics-based search was carried out for metastasis-related proteins in colorectal cancer by analyzing the differential expression of proteins in primary versus metastasis focus-derived colorectal tumor cells. Protein expression profiles were determined using a tissue microarray (TMA), and the results identified Rho GDP-dissociation inhibitor alpha (Rho GDI) as a metastasis-related protein in colon and prostate cancer patients. Consequently, Rho GDI may be useful as a diagnostic biomarker and/or a therapeutic to prevent colon and prostate cancer metastasis.

PMID: 22530308 [PubMed - indexed for MEDLINE]

CEACAM1 in malignant melanoma: a diagnostic and therapeutic target.

Curr Top Med Chem. 2012;12(1):3-10

Authors: Sapoznik S, Ortenberg R, Schachter J, Markel G

Abstract
CEACAM1 adhesion molecule is broadly expressed, participates in pivotal cellular and immunological processes and is involved in cancer. Originally identified as a tumor suppressor, it is now known that in several cancers, including malignant melanoma, CEACAM1 expression correlates with tumor progression and poor survival. Here we review the findings connecting CEACAM1 to malignant melanoma, encompassing in-vitro, in-vivo and patients-derived data. A CEACAM1-mediated mechanism used by melanoma cells to evade immune attack is described in detail. Finally, the potential value of CEACAM1 as a melanoma biomarker and therapeutic target is being discussed.

PMID: 22196267 [PubMed - indexed for MEDLINE]

Gradually implemented new biomarkers for prognostication of breast cancer: complete case analysis may introduce bias.

J Clin Epidemiol. 2012 May;65(5):568-71

Authors: Bhoo Pathy N, Uiterwaal CS, Taib NA, Verkooijen HM, Yip CH

Abstract
OBJECTIVE: Many recent studies investigated the prognostic value of new biomarkers in breast cancer using data from cancer registries. Some of these studies were conducted using only patients for whom biomarker status was available (or tested). Using human epidermal growth factor receptor 2 (HER2) as an example, we determined whether testing for a recently introduced biomarker was associated with the outcome of women with breast cancer.
STUDY DESIGN AND SETTING: We included 910 women with newly diagnosed breast cancer in a tertiary academic hospital in Kuala Lumpur, Malaysia, between 2005 and 2007. Individual 2-year absolute mortality risk was estimated using Cox regression analysis. Logistic regression was used to assess the association between the absolute mortality risk and assessment of HER2 status.
RESULTS: There was a significant inverted U-shaped association between predicted mortality risk and HER2 status determination. Compared with patients with the lowest predicted mortality risk (quintile 1), patients with highest predicted mortality risk (last quintile) were significantly less likely to be tested for HER2 status, whereas those with intermediate predicted mortality risk (quintile 3) were more likely to be tested.
CONCLUSION: Breast cancer prognostication using only patients with available biomarker status may lead to invalid results.

PMID: 22269329 [PubMed - indexed for MEDLINE]

Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer.

Breast Cancer Res Treat. 2012 Feb;131(3):1061-6

Authors: Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow S, Brachtel EF, Schapira L, Come SE, Winer EP, Partridge AH

Abstract
Prior studies have suggested a higher prevalence of high grade, ER-negative, HER2-positive, and basal-like carcinomas in young women with breast cancer. However, the precise distribution of poor prognostic features in this population remains unclear. We examined the pathologic features and distribution of molecular phenotype in relation to patient age in a large group of young women (≤40 years) with invasive breast cancer. Medical records were reviewed for clinical characteristics, tumor stage, and receptor status. Pathologic features, including those features associated with basal-like carcinomas, were examined by central review. Using tumor grade and biomarker expression, cancers were categorized as luminal A (ER+ and/or PR+ and HER2-, histologic grade 1 or 2); luminal B (ER+ and/or PR+ and HER2+, or ER and/or PR+, HER2- and grade 3); HER2 (ER and PR- and HER2+); and triple negative (ER-, PR-, and HER2-). Among 399 women of ≤40 years, 33% had luminal A tumors, 35% luminal B, 11% HER2 (ER-negative), and 21% triple negative. Compared to published results for all breast cancers, a greater proportion of young women had luminal B tumors, and a lesser proportion had luminal A. There were no significant differences in molecular phenotype, tumor stage or grade among the different age groups of young women. However, this population of young women presented with a different distribution of molecular phenotypes compared to the general population of women with breast cancer. These findings may have implications with regard to the etiology and prognosis of breast cancer in young women.

PMID: 22080245 [PubMed - indexed for MEDLINE]

A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Breast Cancer Res Treat. 2012 Feb;131(3):915-24

Authors: Higgins MJ, Prowell TM, Blackford AL, Byrne C, Khouri NF, Slater SA, Jeter SC, Armstrong DK, Davidson NE, Emens LA, Fetting JH, Powers PP, Wolff AC, Green H, Thibert JN, Rae JM, Folkerd E, Dowsett M, Blumenthal RS, Garber JE, Stearns V

Abstract
Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.

PMID: 22076478 [PubMed - indexed for MEDLINE]