abstract: Serum HE4 as a diagnostic and prognostic marker for lung cancer (study included ovarian cancer patients)

Abstract

We evaluated the diagnostic and prognostic efficacy of human epididymis protein 4 (HE4) for lung cancer patients by using our novel enzyme-linked immunosorbent assay (ELISA) system. We measured serum HE4 levels of cancer patients including 49 lung cancer and 18 ovarian cancer patients. Furthermore, we evaluated the relationship between serum HE4 levels and overall survival after chemotherapy of 24 lung cancer patients. Serum HE4 levels were significantly higher for non-small, small cell lung cancer and ovarian cancer patients than for healthy controls. The area under the receiver operating characteristic curve (AUC) was calculated for differentiation of lung cancer patients and healthy controls. AUC for serum HE4 was 0.988 for differentiating lung cancer patients from healthy controls, with a cutoff value of 6.56 ng/ml (sensitivity = 89.8%, specificity = 100%).
Serum HE4 levels were elevated in 36/40 (90.0%) non-small cell lung cancer patients, 8/9 (88.9%) small cell lung cancer patients and 8/18 (44.4%) ovarian cancer patients. High levels of serum HE4 (>15 ng/ml) after chemotherapy were significantly correlated with worse overall survival after the treatment. These findings suggest that serum HE4 is a potential diagnostic and prognostic marker for lung cancer patients.

abstract: Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies

Abstract

Circulating, cell-free microRNAs (miRNAs) hold great promise as a new class of cancer biomarkers due to their surprisingly high stability in plasma, association with disease states, and ease of sensitive measurement. Yet little is known about the origin of circulating miRNAs in either healthy or sick people or what factors influence levels of circulating miRNA biomarkers. Of 79 solid tumor circulating miRNA biomarkers reported in the literature, we found that 58% (46 of 79) are highly expressed in one or more blood cell type. Plasma levels of miRNA biomarkers expressed by myeloid (e.g., miR-223, miR-197, miR-574-3p, and let-7a) and lymphoid (e.g., miR-150) blood cells tightly correlated with corresponding white blood cell counts. Plasma miRNA biomarkers expressed by red blood cells (e.g., miR-486-5p, miR-451, miR-92a, and miR-16) could not be correlated to red cell counts due to limited variation in hematocrit in the cohort studied but were significantly increased in hemolyzed specimens (20- to 30-fold plasma increase; P < 0.0000001). 

Finally, in a patient undergoing autologous hematopoietic cell transplantation, plasma levels of myeloid- and lymphoid-expressed miRNAs (miR-223 and miR-150, respectively) tracked closely with changes in corresponding blood counts. We present evidence that blood cells are a major contributor to circulating miRNA and that perturbations in blood cell counts and hemolysis can alter plasma miRNA biomarker levels by up to 50-fold.  

Given that a majority of reported circulating miRNA cancer biomarkers are highly expressed in blood cells, we suggest caution in interpretation of such results as they may reflect a blood cell-based phenomenon rather than a cancer-specific origin. Cancer Prev Res; 5(3); 1–6. ©2011 AACR.

Clinical Oncology News - Finding an Avastin (Bevacizumab) Biomarker: An Elusive Target

"On a basic level, it is still somewhat unclear why bevacizumab works on some cancers and not on others because seemingly, all tumors need to be fed by blood vessels."

press release: The Clearity Foundation - Molecular profiling reveals differences between primary and recurrent ovarian cancers

Analysis of tumor specimens uncovers changes in biomarker expression that may have implications for therapy selection for women with recurrent ovarian cancer

 "These results demonstrate the dynamic genetic changes in ovarian cancers between diagnosis and recurrence. While the expression of these and other candidate response biomarkers should be evaluated in larger studies to better understand the clinical utility of profiling recurrent tumor specimens, this report highlights our urgent need to individualize our treatment approaches in order to improve ovarian cancer survival," says Dr. Karlan, Director of the Cedars-Sinai Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute and a renowned expert in the field of gynecologic oncology.

".....Ovarian cancers are very different from patient to patient, which means they are likely to respond differently to FDA-approved and investigational drugs. By identifying the alterations in each tumor's information pathways, molecular profiling enables the individualization of a patient's treatment by matching those tumor alterations with one or more drugs. The Clearity Foundation has developed a process for generating this personalized diagnostic information using commercially-available molecular profiling technologies and then analyzing the results using its Diane Barton Database."

 

 

open access: Chinese Medical Journal - Evaluation of whether serum tumor markers in patients with epithelial ovarian carcinoma change following chemotherapy

Blogger's Note: the pdf version is easier to view


Fulltext PDF(314K) Free

"The ratios of CA-125/CP2 and CA-125/CA19-9 were significantly different after either chemotherapy or recurrence." 

"With respect to the pathological type, there were 20 cases of serous carcinoma, 6 cases of mucinous carcinoma, 3 cases of
endometrial carcinoma, 2 cases of clear cell carcinoma
and 4 cases of mixed epithelial carcinoma in the 35 cases
of de novo patients. 

For the recurrent patient group there were 25 cases of serous carcinoma, 4 cases of mucinous carcinoma, 2 cases of endometrial carcinoma, 2 cases of clear cell carcinoma, 1 case of mixed epithelial carcinoma, 2 cases of transitional cell carcinoma and 1 case of undifferentiated carcinoma in the 37 cases of recurrent patients."

Conclusions Serum tumor marker expression in patients with EOC or PSPC may change after chemotherapy or recurrence, indicating that in addition to the markers that are abnormal before surgery, those markers that are normal
should also be monitored during chemotherapy and follow-up.

Picture this: The new imaging techniques that can help doctors select the right treatment at the right time - Cutting Edge - Cancer World (eg. MRI/PET/CT/therapies/biomarkers....)

Blogger's Note: worth reading

abstract: Prognostic Value of Biomarkers Related to Drug Resistance in Patients with Advanced Epithelial Ovarian Cancer

Prognostic Value of Biomarkers Related to Drug Resistance in Patients with Advanced Epithelial Ovarian Cancer:

Background/Aim:
We aimed to investigate the prognostic value of biomarkers [Ki-67, adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), adenosine triphosphate-binding cassette sub-family C member 1 (ABCC1), adenosine triphosphate-binding cassette sub-family C member 2 (ABCC2), p53, cyclin E and v-akt murine thymoma viral oncogene homolog 2 (AKT2)] in patients with advanced epithelial ovarian cancer (EOC).

Materials and Methods:
The levels of expression of biomarkers in tumor tissues of 47 patients with stage 3 or 4 EOC were estimated via immunohistochemical staining using tissue microarrays. The associations of biomarker expression with progression-free survival (PFS) and overall survival (OS) were evaluated using a log-rank test and Cox regression analysis.

Results:
Based on multivariate analysis, high expression of Ki-67 (p=0.003) and low expression of ABCC2 (p=0.048) were associated with a prolonged PFS. However, other biomarkers were not associated with PFS. Residual tumor <1 cm (p=0.023) and PFS >6 months (p=0.005) were associated with prolonged OS. However, none of the biomarkers were associated with OS. 

Conclusion: High expression of Ki-67 and low expression of ABCC2 appear to be useful as markers for prolonged PFS in patients with advanced EOC.

abstract: Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients.

Abstract

"The validation of prognostic biomarkers in large independent patient cohorts is a major bottleneck in ovarian cancer research. We implemented an online tool to assess the prognostic value of the expression levels of all microarray quantified genes in ovarian cancer patients. First, a database was set up using gene expression data and survival information of 1,287 ovarian cancer patients downloaded from GEO and TCGA (Affymetrix HGU133A, HGU133A 2.0 and HGU133+2 microarrays).

After quality control and normalization only probes present on all three Affymetrix platforms were retained (n=22,277). To analyze the prognostic value of the selected gene, the patients are divided into two groups according to various quantile expressions of the gene. These groups are then compared using progression free survival (n=1,090) or overall survival (n=1,287). A Kaplan-Meier survival plot is generated and significance is computed. The tool can be accessed online at www.kmplot.com/ovar. We used this integrative data analysis tool to validate the prognostic power of 37 biomarkers identified in the literature.

Of these, CA125 (p=3.7e-5, HR=1.4), CDKN1B (p=5.4e-5, HR=1.4), KLK6 (p=0.002,HR=0.79), IFNG (p=0.004, HR=0.81), P16 (p=0.02, HR=0.66) and BIRC5 (p=0.00017, HR=0.75) were associated with survival. The combination of several probe sets can further increase prediction efficiency.

In summary, we developed a global online biomarker validation platform that mines all available microarray data to assess the prognostic power of 22,277 genes in 1,287 ovarian cancer patients.

We specifically used this tool to evaluate the effect of 37 previously published biomarkers on ovarian cancer prognosis."

open access: Review - 2010 Targeted Therapies in Epithelial Ovarian Cancer

Review

Targeted Therapies in Epithelial Ovarian Cancer

Download PDF Full-Text

Abstract:

Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life.

In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

Jan 20th: open access: Journal of Ovarian Research IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer - papillary serous tumors; note reference to Hispanic women (Italy/US study)

Background (pdf file)
"Epithelial Ovarian Cancer (EOC) is the most lethal female reproductive tract malignancy with nearly 200,000 new cases and >125,000 deaths attributable to the disease each year worldwide (1).........The search for reliable, specific, and sensitive serum-based biomarkers for EOC
has a long history and its major highlight remains the identification of CA125 nearly 30 years ago (4)."

"Papillary serous tumor samples were collected across all stages (five stage I/II, 11 stage III/IV, two disseminated peritoneal lesions, and two recurrent tumors). For comparison, two borderline tumors were also sequenced."

Research

IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer.

Journal of Ovarian Research 2012, 5:3 doi:10.1186/1757-2215-5-3
Published: 20 January 2012

Abstract (provisional)

Background

We sought to identify candidate serum biomarkers for the detection and surveillance of EOC. Based on RNA-Seq transcriptome analysis of patient-derived tumors, highly expressed secreted proteins were identified using a bioinformatic approach.

Methods

RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes.......... Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA.....

Results

Insulin-like growth factor binding protein (IGFBP-4) was consistently present in the top 7.5% of all expressed genes in all tumor samples. We then screened serum samples to determine if increased tumor expression correlated with serum expression. In an initial discovery set of 21 samples, IGFBP-4 levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (82 controls, 78 cases), IGFBP-4 levels were significantly increased (p<5x10-5). IGFBP-4 levels were ~3x greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients.

Conclusions

This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in ovarian cancer patients.  

Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies. 

pdf: 
Future studies are planned primarily to increase sample size and diversity of patients. Unexpectedly, we noted that Hispanic cases have significantly higher serum IGFPB-4 levels compared to other non-Hispanic cases or all controls . We are unaware of previous reports or studies suggesting a biologic basis for this finding. Thus, this intriguing finding will be specifically explored in future studies.

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The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

open access Frontiers | Epigenomics of Ovarian Cancer and Its Chemoprevention | Frontiers in Epigenomics

.......Due to the atypical syndrome of the early stage of ovarian cancer, it is difficult to diagnose in its early stages. By the time most ovarian cancers are diagnosed, they are already at stage III or IV. The two most significant obstacles to the effective treatment of ovarian cancers are the lack of early diagnostic markers and the development of drug resistance after therapeutic treatment of advanced disease. Ovarian cancer screening with transvaginal ultrasound (TVU) and CA125 was evaluated in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial, however, it was revealed that the predictive value of both tests was relatively low (Buys et al., 2005). Increasing evidence indicates that epigenetic mechanisms may play a major role in the development of ovarian cancer..........
In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies........

Serum Levels of the Ovarian Cancer Biomarker HE4 are decreased in Pregnancy and Increase with Age

Objectives:

To establish normal ranges for HE4 serum levels in healthy women.

Proteomic biomarkers in combination with CA 125 for detection of epithelial ovarian cancer using prediagnostic serum samples from the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial

RESULTS:

CA 125 levels were elevated (≥35 U/mL) in 61.5% of 65 patients who had CA 125 data available from samples that were collected <12 months before cancer diagnosis; however, levels of the additional 7 biomarkers were not different between cases and the 3 control groups individually or combined. Two panels that combined CA 125 and the 7 biomarkers failed to improve the sensitivity of CA 125 alone.

CONCLUSIONS:

In contrast to earlier findings from analyzes of postdiagnostically collected sera, the addition of 7 biomarkers to CA 125 did not improve sensitivity for preclinical diagnosis beyond CA 125 alone.

Search Results: 'biomarkers' 'ovarian' 2011 ASCO Abstracts

Find ALL words: biomarkers ovarian

Found 22 documents

Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-analyses — JAMA

Context Many biomarkers are proposed in highly cited studies as determinants of disease risk, prognosis, or response to treatment, but few eventually transform clinical practice.

Objective To examine whether the magnitude of the effect sizes of biomarkers proposed in highly cited studies is accurate or overestimated.................

Conclusion Highly cited biomarker studies often report larger effect estimates for postulated associations than are reported in subsequent meta-analyses evaluating the same associations. 

Author Insights: Beware of Overestimating Biomarker Validity - JAMA

abstract: Calculator for ovarian carcinoma subtype prediction : Modern Pathology

Abstract:

With the emerging evidence that the five major ovarian carcinoma subtypes (high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous) are distinct disease entities, management of ovarian carcinoma will become subtype specific in the future.

In an effort to improve diagnostic accuracy, we set out to determine if an immunohistochemical panel of molecular markers could reproduce consensus subtype assignment.

Immunohistochemical expression of 22 biomarkers were examined on tissue microarrays constructed from 322 archival ovarian carcinoma samples from the British Columbia Cancer Agency archives, for the period between 1984 and 2000, and an independent set of 242 cases of ovarian carcinoma from the Gynaecologic Tissue Bank at Vancouver General Hospital from 2001 to 2008. Nominal logistic regression was used to produce a subtype prediction model for each of these sets of cases. These models were then cross-validated against the other cohort, and then both models were further validated in an independent cohort of 81 ovarian carcinoma samples from five different centers.

Starting with data for 22 markers, full model fit, backwards, nominal logistic regression identified the same nine markers (CDKN2A, DKK1, HNF1B, MDM2, PGR, TFF3, TP53, VIM, WT1) as being most predictive of ovarian carcinoma subtype in both the archival and tumor bank cohorts. These models were able to predict subtype in the respective cohort in which they were developed with a high degree of sensitivity and specificity (κ statistics of 0.88±0.02 and 0.86±0.04, respectively).

When the models were cross-validated (ie using the model developed in one case series to predict subtype in the other series), the prediction equation's performances were reduced (κ statistics of 0.70±0.04 and 0.61±0.04, respectively) due to differences in frequency of expression of some biomarkers in the two case series. Both models were then validated on the independent series of 81 cases, with very good to excellent ability to predict subtype (κ=0.85±0.06 and 0.78±0.07, respectively).

A nine-marker immunohistochemical maker panel can be used to objectively support classification into one of the five major subtypes of ovarian carcinoma.

open access journal: Journal of Ovarian Research Differential hRad17 expression by histologic subtype of ovarian cancer

Background
In the search for unique ovarian cancer biomarkers, ovarian specific cDNA microarray analysis identified hRad17, a cell cycle checkpoint protein, as over-expressed in ovarian cancer. The aim of this study was to validate this expression.

Methods
Immunohistochemistry was performed on 72 serous, 19 endometrioid, 10 clear cell, and 6 mucinous ovarian cancers, 9 benign ovarian tumors, and 6 normal ovarian tissue sections using an anti-hRad17 antibody. Western blot analysis and quantitative PCR were performed using cell lysates and total RNA prepared from 17 ovarian cancer cell lines and 6 normal ovarian epithelial cell cultures (HOSE).


Results
Antibody staining confirmed upregulation of hRad17 in 49.5% of ovarian cancer cases. Immunohistochemistry demonstrated that only 42% of serous and 47% of endometrioid subtypes showed overexpression compared to 80% of clear cell and 100% of mucinous cancers.

Conclusions
hRad17 is over-expressed in ovarian cancer. This over-expression varies by subtype suggesting a role in the pathogenesis of these types. Functional studies are needed to determine the potential role of this protein in ovarian cancer.

 PDF

No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting

of interest: "HE4 was not elevated in endometriosis"
CONCLUSIONS:
The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.

financial news: Healthcare Stock on Watch; Vermillion (OVA1) climbs on Poster Presentation | Beacon Equity: Penny Stocks, Stock Alerts

Healthcare Stock on Watch; Vermillion climbs on Poster Presentation

Posted by g.zalesak on Mar 08, 2011

Vermillion Inc. (NASDAQ: VRML) shares are up nearly 2.5% to $4.99 mid-day on word of the company’s poster presentation of its preliminary results from its collaboration with John Hopkins University School of Medicine to identify biomarkers that improve the identification of malignant ovarian tumors.
The poster evaluated more than 20 candidate biomarkers for their ability to complement the company’s CA125 in distinguishing benign ovarian tumors from malignant ones.