paywalled: Two-marker Combinations for Preoperative Discrimination of Benign and Malignant Ovarian Masses

Two-marker Combinations for Preoperative Discrimination of Benign and Malignant Ovarian Masses

Abstract

Background: 

When caring for patients with ovarian neoplasms, correct preoperative discrimination of benign and malignant disease is deemed vital. In this study, we tested serum biomarkers' alone and in combination, to achieve this aim.

Conclusion: 

A combination of CA-125 with HE4 could facilitate the identification of women at risk for ovarian cancer.

paywalled: Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.

Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.:


ABSTRACT:

More than 200,000 women undergo exploratory surgery for a pelvic mass in the United States each year and 13%-21% of pelvic lesions are found to be malignant. Individual reports and meta-analysis indicate better outcomes when cancer surgery is performed by gynecologic oncologists. Despite the advantages provided by more thorough staging and cytoreductive surgery, only 30%-50% of women with ovarian cancer are referred to surgeons with specialized training in the United States. Imaging, menopausal status and biomarkers can aid in distinguishing malignant from benign pelvic masses to inform decisions regarding appropriate referral. The risk of malignancy index (RMI) uses ultrasound, menopausal status and CA125 and has been utilized in the United Kingdom for two decades, providing sensitivity that has ranged from 71%-88% and specificity it from 97%-74% for identifying patients with malignant disease. Criteria have been established by the Society of Gynecology Oncology and American College of Obstetrics and Gynecology for referral to a gynecologic oncologist, but these have lower sensitivity and specificity than the RMI.

Recently, two new algorithms have been developed to identify women at sufficiently high risk to prompt referral to a specialized surgeon. The OVA1 multivariate index incorporates imaging, menopausal status, CA125 and four other proteomic biomarkers. Use of OVA1 provides 85%-96% sensitivity at 28%-40% specificity depending upon menopausal status. The negative predictive value for women judged to be at low risk is 94%-96%.

The risk of malignancy algorithm (ROMA) includes CA125, human epididymal protein 4 and menopausal status, but not imaging results.

ESO: e-grandround May 24th: Biomarkers and candidate therapeutics in ovarian cancer pipeline

Biomarkers and candidate therapeutics in ovarian cancer pipeline

European School Oncology
Online educational resources

• ESO

e-grandround

Biomarkers and candidate therapeutics in ovarian cancer pipeline ^{CME accredited}

e-grandround GR197 - 24 May 2012 - 18:15-19:00 CET

Expert: Hani Gabra, Imperial College, London, United Kingdom
Discussant: Margaret Hutka, Royal Marsden Hospital, Sutton, United Kingdom

The live session starts in about 9 days

Access to the live session is open 15 minutes before the start of the session

Submit your question in advance

An In Vitro Diagnostic Multivariate Index Assay (IVDMIA) for Ovarian Cancer: Harvesting the Power of Multiple Biomarkers (OVA1)

An In Vitro Diagnostic Multivariate Index Assay (IVDMIA) for Ovarian Cancer: Harvesting the Power of Multiple Biomarkers

Dr. Zhang is the inventor of the OVA1 algorithm, and as such is entitled to royalty payments from the sale of OVA1® through a license agreement between Johns Hopkins University and Vermillion, Inc.

Main Points

• The advantages of an in vitro diagnostic multivariate index assay (IVDMIA) in comparison to a single biomarker assay are based on the premise that the single-valued index, with its aggregated information from complementary biomarkers, will outperform each of its component biomarkers used individually.
• The ability of multivariate models to capture complex patterns in high-dimensional data also means that non-disease-related artifacts that happen to confound the samples used to train the models will also be captured.
• The inclusion of biomarkers in an IVDMIA requires that they are complementary, and that they collectively outperform a single marker with respect to the test’s intended use.
• OVA1® (Vermillion, Inc., Austin, TX) combines results from five tests—CA-125 II, prealbumin, apolipoprotein A-1, β2-microglobulin, and transferrin—into a single-valued index between 0 and 10; a higher value corresponds to a higher risk of malignancy.
• The addition of OVA1 to clinical assessment brings significant improvement in sensitivity. This is, however, at the cost of a reduced specificity. During the construction of the OVA1 multivariate model and the choice of cutoff values, a conscious decision was made to emphasize the need for a high sensitivity. This decision took into consideration the need to mitigate the safety concern of OVA1 with respect to its predefined intended use. Because OVA1 is to be used prior to the decision to refer to a specialist, a high sensitivity minimizes the risk of false-negative results for patients who actually have malignant diseases.

Myriad RBM Announces the Launch of OncologyMAP® v. 2.0

Myriad RBM Announces the Launch of OncologyMAP® v. 2.0

Myriad Genetics (NASDAQ: MYGN) announced today that Myriad RBM, a wholly owned subsidiary of Myriad Genetics, has launched OncologyMAP® v. 2.0, a powerful research tool developed with funding and direction from the National Cancer Institute and the Cancer Prevention Research Institute of Texas. OncologyMAP® v. 2.0 is a comprehensive, cost-effective testing service that builds on the success of the original OncologyMAP® service by increasing the scope and diversity of biomarker analysis for drug re-tasking, indication expansion, and patient stratification studies and provides researchers with the ability to accelerate the pace of discovery, validation, and translation of cancer biomarkers into clinically useful tests......................

paywalled: Physical Activity, Biomarkers, and Disease Outcomes in Cancer Survivors: A Systematic Review

Physical Activity, Biomarkers, and Disease Outcomes in Cancer Survivors: A Systematic Review:

Background
Cancer survivors often seek information about how lifestyle factors, such as physical activity, may influence their prognosis. We systematically reviewed studies that examined relationships between physical activity and mortality (cancer-specific and all-cause) and/or cancer biomarkers.

Methods
We identified 45 articles published from January 1950 to August 2011 through MEDLINE database searches that were related to physical activity, cancer survival, and biomarkers potentially relevant to cancer survival. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement to guide this review. Study characteristics, mortality outcomes, and biomarker-relevant and subgroup results were abstracted for each article that met the inclusion criteria (ie, research articles that included participants with a cancer diagnosis, mortality outcomes, and an assessment of physical activity).

Results
There was consistent evidence from 27 observational studies that physical activity is associated with reduced all-cause, breast cancer–specific, and colon cancer–specific mortality. There is currently insufficient evidence regarding the association between physical activity and mortality for survivors of other cancers. Randomized controlled trials of exercise that included biomarker endpoints suggest that exercise may result in beneficial changes in the circulating level of insulin, insulin-related pathways, inflammation, and, possibly, immunity; however, the evidence is still preliminary.

Conclusions
Future research directions identified include the need for more observational studies on additional types of cancer with larger sample sizes; the need to examine whether the association between physical activity and mortality varies by tumor, clinical, or risk factor characteristics; and the need for research on the biological mechanisms involved in the association between physical activity and survival after a cancer diagnosis. Future randomized controlled trials of exercise with biomarker and cancer-specific disease endpoints, such as recurrence, new primary cancers, and cancer-specific mortality in cancer survivors, are warranted.

Journal of Experimental & Clinical Cancer Research | Abstract | Circulating microRNAs in cancer: origin, function and application

Journal of Experimental & Clinical Cancer Research | Abstract | Circulating microRNAs in cancer: origin, function and application

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

  Review

Circulating microRNAs in cancer: origin, function and application

Journal of Experimental & Clinical Cancer Research 2012, 31:38 doi:10.1186/1756-9966-31-38


Published: 30 April 2012

Abstract (provisional)

MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. The dysregulation of miRNAs has been linked to a series of diseases, including various types of cancer. Since their discovery in the circulation of cancer patients, there has been a steady increase in the study of circulating miRNAs as stable, non-invasive biomarkers. However, the origin and function of circulating miRNAs has not been systematically elucidated. In this review, we summarize the discovery of circulating miRNAs and their potential as biomarkers. We further emphasize their possible origin and function. Finally, we discuss the application and existing questions surrounding circulating miRNAs in cancer diagnostics. Although several challenges remain to be concerned, circulating miRNAs could be useful, non-invasive biomarkers for cancer diagnosis.

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

Biomarkers in the circulation

"Circulating biomarkers undoubtedly play an increasingly significant role in clinicalapplications such as disease diagnostics, monitoring therapeutic effect and predicting recurrence in cancer patients. The currently used fluid-based biomarkers are primarily proteins, such as alpha-fetoprotein (AFP) [8], chromogranin A (CgA) [9], nuclear matrix
protein 22 (NMP 22) [10], carbohydrate antigen 125 (CA 125) [11]; enzymes, such as prostate specific antigen (PSA) [12]; and human chorionic gonadotropin (hCG) [13]. While these biomarkers provide an opportunity to analyze tumors comprehensively in an invasive
way, low sensitivity and specificity limit their clinical application. For example, serum levels of AFP are often elevated in hepatocellular carcinoma (HCC); however, this is also the case in germ cell tumors, gastric, biliary and pancreatic cancers.......

 reference/cited (google):

23. Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE: The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol 2009, 112:55–59. 

 

paywalled: Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer.

Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer.

Abstract

The aim of this study was to investigate the role of biomarkers CA125, HE4, and CA72.4 at diagnosis and throughout the follow-up in patients with epithelial ovarian cancer (EOC). Thirty-nine patients with EOC were deemed eligible, and 20 were followed up. CA125, HE4, and CA72.4 serum levels were determined for all patients at initial diagnosis of EOC. Among these patients, the number of cases with an elevated level of each individual marker was CA125 77 %, HE4 85 %, and CA72.4 72 %. A statistically significant difference was observed between the level of HE4 when compared to CA72.4 (p < 0.02). In the follow-up phase, we observed tumor marker levels fluctuating according to response to chemotherapy. When combining two out of the three biomarkers together, we observed increased values of CA125 and CA72.4 in 55 % of the patients, increased values of CA125 and HE4 in 65 % of the patients, and finally increased HE4 and CA72.4 in 75 % of the patients. A statistically significant difference was observed when combining HE4 and CA72.4, but not CA125 and CA 72.4 (p < 0.002). In conclusion, our study demonstrates that the association of three biomarkers CA125, HE4, and CA72.4 provides a valuable contribution in the follow-up of EOC patients.

paywalled: Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology

Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology

Current Opinion in Oncology:

May 2012 - Volume 24 - Issue 3 - p 316–324

doi: 10.1097/CCO.0b013e32835280c6

INNOVATIVE EARLY CLINICAL TRIALS METHODOLOGY AND NEW THERAPEUTICS IN CANCER: Edited by Ahmad Awada

Targeting the DNA damage response in oncology: past, present and future perspectives

Abstract

Purpose of review: 

The success of poly(ADP-ribose) polymerase inhibition in BRCA1 or BRCA2 deficient tumors as an anticancer strategy provided proof-of-concept for a synthetic lethality approach in oncology. There is therefore now active interest in expanding this approach to include other agents targeting the DNA damage response (DDR). We review lessons learnt from the development of inhibitors against DNA damage response mechanisms and envision the future of DNA repair inhibition in oncology.

press release: (OVA1) Vermillion Receives Notice of Allowance for Patent of Biomarker for Ovarian Cancer

Vermillion Receives Notice of Allowance for Patent of Biomarker for Ovarian Cancer


(press release) About OVA1
OVA1 is a blood test for pre-surgical assessment of ovarian tumors for malignancy, using a unique multi-biomarker approach. In a published clinical trial, OVA1 achieved 99% sensitivity in detecting epithelial ovarian cancers (EOC). This included 96% sensitivity for stage I EOC, the earliest and most curable EOC stage, compared with 57% for the conventional biomarker CA125.(1) In addition, OVA1 found 70% of malignancies missed by non-specialist pre-surgical assessment,(1) and it increased detection of malignancy over ACOG guidelines from 77% to 94%.(2) As the first protein-based, In Vitro Diagnostic Multi-Variate Index Assay (IVDMIA) cleared by the FDA, OVA1 also represents a new class of software-based diagnostics.

Clinical trial designs for testing biomarker-based personalized therapies

Clinical trial designs for testing biomarker-based personalized therapies

Abstract:

Background
Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues...


Conclusion
Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies.

Abstract - Biotargets of Cancer in Current Clinical Practice - Ovarian Cancer

 Medicine

Biotargets of Cancer in Current Clinical Practice

Current Clinical Pathology, 2012, 381-401, DOI: 10.1007/978-1-61779-615-9_14

Abstract -
  
Abstract

Ovarian cancer is the fifth most common cancer in women and is the most lethal of all gynecologic cancers. Early-stage ovarian cancer is curable while women who are diagnosed with advanced ovarian cancer continue to have poor long-term survival due to recurrence of disease. Unfortunately, most women are diagnosed with advanced-stage disease. Early detection is a primary objective for clinicians and scientists, yet single modality (CA-125, transvaginal ultrasound) screening tests have been ineffective. More recent novel approaches combining modalities and utilizing serial serum sampling are being tested and hold great promise. In addition, the recent application of proteomics to this clinical question has the potential to identify new and important biotargets.

Unfortunately, the majority of ovarian cancer patients have advanced-stage disease, and although most will die of their disease, their survival is quite heterogenous (different). 

The ability to stratify patients according to prognosis could help guide therapy. The current “gold standard” for prognosis uses patient, surgical, and tumor characteristics, yet these have the tendency to be notoriously inaccurate. This prognostic uncertainty and the drive to identify predictive factors by which we can select novel and targeted therapy have stimulated researchers to look beyond traditional markers and test and validate molecular and genomic biomarkers, which are anticipated to soon complement or even eclipse traditional factors clarifying prognosis and select treatments. 

For patients with advanced-stage disease, a multitude of prognostic factors have been characterized. While promising, none of these biotargets have been validated at present to be clinically useful. More recent application of genomic technologies is likely to yield clinically relevant signatures and/or biotargets which will provide the basis for personalization of care for these patients.

Optimizing Molecular-Targeted Therapies in Ovarian Cancer: The Renewed Surge of Interest in Ovarian Cancer Biomarkers and Cell Signaling Pathways : Table 1 (eg. HE4....)

Blogger's Note: the table includes biomarkers for ovarian cancer in research

Optimizing Molecular-Targeted Therapies in Ovarian Cancer: The Renewed Surge of Interest in Ovarian Cancer Biomarkers and Cell Signaling Pathways : Table 1

original article previously posted - link:
Journal of Oncology

Blogger's Opinion: repost (2011) : 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 - Moore - 2011 - Cancer - Wiley Online Library

Blogger's Note/Opinion:  
efforts to improve on the existing CA125 biomarkers remain elusive, as we speak;  this may be confirmed by the multitude of research studies/meta-analsyes (known issues); we, as patients/survivors, all have examples which are contrary, or exceptions,  to what is presently known and therefore the issue of 'personalized medicine'; biomarker banking (tissues from surgery for research) is an important key element for those diagnosed so that we may move forward beyond the standard CA125 (as one example); on the bonus side - research is moving forward at a greatly accelerated pace (molecular/proteomics...) but the research is still in the phase/s of being brought to the 'clinic',  meaning what actually works for our ovarian cancer women pre-present-post diagnosis; it is a common philosophy in ovarian cancer research that due to our low numbers (relative to other cancers) that we must have global research (not least of which is to mention global economics); as patients you can make a difference by ensuring that the clinical studies which you enroll will make a difference in these efforts as opposed to small isolated studies - specifically those that continue to regurgitate past studies which do not move forward beyond the existing eg. psychosocial aspects of prophlactic surgery


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 - Moore - 2011 - Cancer

RESULTS (abstract):

"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."

DISCUSSION

 ".....Although a marginally better performance was observed for the identification of cases at least 6 months before diagnosis using an all-site multimarker panel (which included CA 125, HE4, tumor-associated glycoprotein 72 [CA 72-4], substance P-like immunoreactivity, andβ2M) were observed compared with CA 125 alone, the increase was not statistically significant.²¹ In addition to the current study, 5 additional panels were evaluated, none of which improved on the results with CA 125 alone.8 Considering the failure of multiple biomarkers to improve upon CA 125 in prediagnostic samples, new approaches are badly needed for biomarker discovery. One weakness of the current study is that we were unable to evaluate markers in nonwhite populations because of a very small number of nonwhite cases in the PLCO trial. The results of this combined effort will likely reshape our approach to biomarker discovery and validation. In addition to searching for protein analytes, autoantibodies also may be sought. Finally, previous studies have had limited success in identifying and evaluated autoantibodies of human proteins expressed in bacteria or insect cells. Recent advances in expressing human proteins in human cells could allow the identification of new epitopes that are selective for altered tertiary structure and glycosylation status of selected protein targets."

Future Medicine - Biomarkers in Medicine - numerous items of interest

Future Medicine - Biomarkers in Medicine 

eg.:

Use of molecular diagnostic tests for peripheral neuropathy called into question

Noninvasive test  (ColonSentry^®) for colorectal cancer risk now available in the USA

Virtual tool could aid detection of genetic mutations

Potential advances in the detection of circulating tumor cells with advent of new blood test

 

 

Marker of DNA Damage Could Predict Response to Platinum Chemotherapy

Marker of DNA Damage Could Predict Response to Platinum Chemotherapy:

• Assay could direct treatment options for triple-negative breast cancer.
• Accumulations of telomere AI predicted sensitivity to therapy.

PHILADELPHIA — Scientists have uncovered a marker of DNA damage that could predict who will respond to platinum-based chemotherapy drugs like cisplatin or carboplatin.
These drugs are widely used for ovarian cancer, but as with most cancer drugs, it can be difficult to predict who will respond to therapy.
A team of researchers from the Dana-Farber Cancer Institute found that this marker, telomeric allelic imbalance or tAI, could predict sensitivity to therapy in patients with triple-negative breast cancer.
The results are published in Cancer Discovery, a journal of the American Association for Cancer Research.
“We currently do not have any targeted therapies for patients with triple-negative breast cancer, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward,” said lead pathologist Andrea Richardson, M.D., Ph.D., assistant professor of medicine at Dana-Farber Cancer Institute.
Scientists have long known that DNA repair status is a predictor of sensitivity to therapy and thus prognosis. However, measurements of DNA repair status have been slow to arrive.
Richardson and colleagues looked for genomic signatures in cell lines and tumors and correlated them to platinum sensitivity.
In patients with triple-negative breast cancer, they found that a high level of subchromosomal regions with allelic imbalance extended to the telomere predicted response to cisplatin treatment. The same was true for serous ovarian cancer.
Importantly for patients with triple-negative breast cancer, researchers found an inverse relationship between the level of tAI and BRCA1 expression.

abstract: Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery - Variability of Poly (ADP-Ribose) Polymerase Activity.

Wiki:  Poly ADP ribose polymerase: Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

                   ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 Requirements to Assess Feasibility of Phase 0 Trials during Major Abdominal Surgery - Variability of Poly (ADP-Ribose) Polymerase Activity.

Abstract

Purpose: 

The aim of this study was to evaluate the feasibility of phase 0 trials in the setting of a routine surgical procedure. Logistic considerations, tissue sampling and handling, and variability of a biomarker during surgery, in here activity of poly(ADP-ribose) polymerase, were evaluated. 

Experimental design: 

Patients with highly suspicious or proven diagnosis of advanced ovarian cancer, planned for debulking surgery were asked to allow sequential tumor biopsies during surgery. Biopsies were frozen immediately and poly (ADP-ribose) polymerase activity was measured subsequently. 

Results: 

Baseline biopsies were obtained from eight patients after a median time of 88 minutes (minimum of 50 to maximum of 123 minutes). Second and third biopsies were obtained after a median of 60 (32-96) and 101 (79-130) minutes, respectively. Mean tumor load was 44% (5%-100%), with a cellular viability of 98% (85%-100%). Median baseline PARP activity was 1035 pg/ml (range: 429-2663 pg/ml). The observed inter-patient variability at baseline was large: standard deviation was 769 before and 0.59 after natural log transformation. 

Conclusions: 

Conducting phase 0 trials during surgery seems to be feasible in terms of logistic considerations. In preparation of a phase 0 trial during surgery, a feasibility study like this should be conducted to rule out major interactions of the surgical intervention with respect to the targeted biomarker.

abstract: Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers

Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers:

Molecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for-purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. 

abstract: Leveling the Playing Field: Bringing Development of Biomarkers and Molecular Diagnostics up to the Standards for Drug Development

Leveling the Playing Field: Bringing Development of Biomarkers and Molecular Diagnostics up to the Standards for Drug Development

 "....One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts."

abstract: Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125 (includes graphic/study of 23 patients)

 Highlights
(in study of 23 patients)

► Three new markers were compared to CA125 for lead time to ovarian cancer recurrence.
► HE4 elevates at recurrence when CA125 does not.
► Mesothelin has less marker potential, MMP7 shows promise and requires confirmation.
  
Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125: Publication year: 2012

Objective 
Evaluate and compare the effectiveness of CA125, HE4, Mesothelin and MMP7 marker levels to monitor ovarian cancer patients after surgery and chemotherapy. Evaluate the lead time of a rise of marker levels before recurrence.

Methods 
The study consists of 23 patients with advanced stage ovarian/fallopian tube cancer. Blood was drawn after front line surgery and chemotherapy treatment and at 3 month intervals thereafter. One patient had chemoresistant disease, two patients remained in remission and 20 patients had recurring disease and were used for marker evaluation.

Results
In five patients HE4 was the only marker to elevate before recurrence with a lead time of up to 4½ months including one patient who did not have a CA125 response at all. In a further two patients, HE4 increased before CA125 did. In four of these seven patients, HE4 levels were consistently at or above threshold during remission when both CA125 and imaging results were negative. MMP7 elevated before recurrence in one patient who was negative for the other markers. Mesothelin elevated in two patients who were also positive for CA125 and HE4.

Conclusions 
HE4 can predict ovarian cancer recurrence earlier than CA125 and it can be elevated in patients that do not express CA125 at sufficient levels to make a clinical decision. MMP7 and Mesothelin have lower potential as markers for ovarian cancer recurrence to complement CA125. A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis.

Graphical Abstract

Highlights

► Three new markers were compared to CA125 for lead time to ovarian cancer recurrence.
► HE4 elevates at recurrence when CA125 does not.
► Mesothelin has less marker potential, MMP7 shows promise and requires confirmation.