At present, no effective screening technique exists for ovarian cancer.  While CA-125 and transvaginal ultrasound have been proposed, particularly in patients at high genetic risk for ovarian cancer, to date these techniques have not resulted in a decrease in morbidity, primarily due to the disease stage at presentation and the lack of curative therapies.  Use of proteomic patterns in serum to identify ovarian cancer is one of the first commercially available clinical applications of proteomics and is the result of a joint project initiated between the National Cancer Institute and the U.S. Food and Drug Administration (FDA) to develop proteomics for early detection and cancer screening.  The OvaCheck® (Correlogic Systems, Inc., Rockville, MD) is based on proteomic patterns detected in the serum, which are further analyzed with the use of a mass spectrometer to profile a population of proteins based on their size and electrical charge.  This type of analysis contains thousands of data points, which undergo further sophisticated computer analysis using artificial intelligence based algorithms to identify a pattern that is consistent with ovarian cancer.  While the OvaCheck® test is the first commercially available cancer screening test using proteomics, there is also interest in developing proteomic screening tests for prostate cancer, breast cancer and gastrointestinal malignancies.

Investigational/Not Medically Necessary:

Analysis of proteomic patterns in serum for screening and detection of ovarian cancer is considered investigational/not medically necessary.

Rationale

While there has been considerable publicity regarding the potential role for proteomics for cancer screening and detection (Conrads, 2003; Wu, 2002; Zhu, 2003), to date there has been one published article in the peer-reviewed literature that has examined the technique for ovarian cancer detection in women considered at high risk of ovarian cancer.  Petricoin and colleagues reported on the technical feasibility of proteomic screening in a test series of serum from 50 patients with and 50 patients without ovarian cancer.  (Petricoin, 2002)  The spectra of proteins were analyzed by an iterative searching algorithm that identified a cluster pattern that segregated the cancer from non-cancer patients.  This discovered pattern was then used to classify an independent set of 116 masked serum samples; 50 from women with ovarian cancer, and 66 from unaffected women or those with non-malignant conditions.  Individuals without cancer were considered at high risk, due either to familial breast or cancer syndrome or the presence of BRCA 1 or BRCA 2 mutations.  All 50 with ovarian cancer were correctly identified, including the 18 with stage I cancer.  Of the 66 benign cases, 63 were identified as not cancer, yielding a sensitivity of 100% and a positive predictive value of 94%.  The authors note that while a positive predictive value of 94% may be acceptable for those high-risk patients, in the larger population of average-risk patients, the positive predictive value must be close to 100% to avoid a high number of false positives, which in turn would generate additional work up.  One of the key outcomes of an ovarian cancer screening test is the ability to identify Stage I ovarian cancer that is potentially curable with surgery.  The above study only included 18 patients with Stage I ovarian cancer.  The authors state that an important future goal is the confirmation of the diagnostic performance of proteomic screening for the prospective detection of Stage I ovarian cancer in trials of both high- and low-risk women.  Such trials are currently underway at the National Cancer Institute.

It should also be noted that the technology used in the Petricoin study (Petricoin, 2002) is not the same as the technology proposed for the OvaCheck® test.  According to the National Cancer Institute, “The two techniques use different mass spectrometry instrumentation and detection methods, as well as different sample handling and processing methods.  Therefore the class of molecules analyzed by these two approaches, and thus the molecule that constitute the diagnostic patterns would be expected to be entirely different.”  (Rosenblatt, 2004)  Other comments and correspondence in the literature also question the statistical analysis used by Petricoin (Diamandis, 2004) and other technical issues.  (Diamandis, 2002)  In February 2004, the Society of Gynecologic Oncologists released the following statement:

The Society of Gynecologic Oncologists (SGO) recognizes the importance of accurate early detection biomarkers for ovarian cancer.  For this reason SGO reviewed the literature regarding OvaCheck®, a serum based diagnostic test for ovarian cancer.  In the opinion of SGO, more research is needed to validate the test’s effectiveness before offering it to the public.  SGO is committed to actively following and contributing to this vitally important research.  As physicians who care only for women with gynecologic cancer, our hope is that these cancers can either be prevented or detected early.  Because no test now exists to routinely detect ovarian cancer in its earliest and most curable stage, we will await the results of further clinical validation of OvaCheck® with great interest.

Background/Overview

While research into the genetic basis of cancer has been an intense research focus, genetic mutations do not reflect the complicated interactions between individual cells, tissue and organs.  Proteins are the functional units of cells and represent the end product of the interactions among the underlying genes.  Therefore, recently there has been increasing research interest in the pattern of proteins associated with malignancies.  This field may be referred to as proteomics (to distinguish it from genomics), defined as the study of all protein forms expressed within an organism as a function of time, age, state and external factors.  Within cancer research, one research application has been the identification of a pattern of proteins detected in a given fluid, such as body fluid or serum, that are associated with an underlying cancer.  Essentially, the identification of patterns of proteins in the serum could function as serum tumor markers, similar in concept to the more familiar prostate specific antigen (PSA) or CA-125, which are used in the detection and monitoring of prostate and ovarian cancer, respectively.

According to the National Cancer Institute (NCI), ovarian cancer is the fifth leading cause of cancer death among US women and has the highest mortality rate of all gynecologic cancers.  It was projected that 20,180 new cases of ovarian cancer will be diagnosed in the United States in 2006, and 15,310 women will die of this disease.  (NCI, 2006)  Ovarian cancer is rarely diagnosed in its early stages.  It is usually quite advanced by the time diagnosis is made.  The outcome is often poor.  Unfortunately, there is no reliable screening test for ovarian cancer, but several large studies are in progress to learn how best to find ovarian cancer in its earliest stage.

Definitions

Algorithm: a set of mathematical rules for solving complex problems with the aid of computer technology 

Proteomics:  the study of molecules in the functional protein pathways of normal or diseased states

Screening: checking or testing for disease when there are no symptoms

Serum: the clear portion of any body fluid, in this case the clear portion of blood

Coding

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Services are Investigational/Not Medically Necessary:
When the code describes a procedure indicated in the Policy section as investigational/not medically necessary.

CPT

ICD-9 Diagnosis

References

Peer Reviewed Publications:

1. Conrads TP, Zhou M, Petricoin EF 3rd, et al. Cancer diagnosis using proteomic patterns. Expert Rev Mol Diagn. 2003; 3(4):411-420.
2. Conrads TP, Fusaro VS, Ross S, et al. High-resolution serum proteomic features for ovarian cancer detection.  Endocr Relat Cancer.  2004; 11(2):163–178.
3. Diamandis EP.  Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems.  J Natl Cancer Inst. 2004; 96(5):353-356.
4. Diamandis EP.  Proteomic patterns in serum and identification of ovarian cancer.  Lancet 2002; 360(9327):169-171. 
5. Petricoin EF, Ardekani AM, Hitt BA, et al. Use of proteomic patterns in serum to identify ovarian cancer.  Lancet 2002; 359(9306):572-577.
6. Rosenblatt KP, Bryant-Greenwood P, Killian JK, et al. Serum proteomics in cancer diagnosis and management.  Annu Rev Med. 2004; 55:97-112.
7. Tchabo NE, Liel MS, Kohn EC. Applying proteomics in clinical trials: assessing the potential and practical limitations in ovarian cancer.  J Pharmacogenomics.  2005; 5(3):141-148.
8. Wu W, Hu W, Kavanagh JJ. Proteomics in cancer research. Int J Gynecol Cancer.  2002; 12(5):409-423.
9. Ye B, Skates S, Mok SC, et al. Proteomic-based discovery and characterization of glycosylated eosinophil-derived neurotoxin and COOH-terminal osteopontin fragments for ovarian cancer in urine.  Clin Cancer Res. 2006; 12(2):432-441.
10. Zhang Z, Bast RC Jr, Yu Y, et al. Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer.  Cancer Res. 2004; 64(16):5882-5890.
11. Zhu W, Wang X, Ma Y, et al Detection of cancer-specific markers amid massive mass spectral data.  Proc Natl Acad Sci. U S A. 2003; 100(25):14666-14671.

Government Agency, Medical Society, and Other Authoritative Publications:

1. National Cancer Institutes.  Questions and Answers: Distinction Between the NCI/FDA Ovarian Cancer Proteomics Research Program and Diagnostic Tests by Private Industry (e.g. OvaCheck ™).  Available at: http://www.cancer.gov/newscenter/pressreleases/ProteomicsOvarian.  Accessed on February 26, 2007. 
2. Society of Gynceologic Oncologists, Chicago, Illinois, Press release: Society of Gynecologic Oncologists statement regarding OvaCheck. February 7, 2004.  Available at: http://www.sgo.org/images/pdfs/policy/OvaCheck_statement.pdf  Accessed on February 26, 2007.
3. U.S. Food and Drug Administration. Center for Devices and Radiological Health.  Office of In Vitro Diagnostic Device Evaluation and Safety. Letter to Correlogic Systems, Inc. July 12, 2004.  Available at: http://www.fda.gov/cdrh/oivd/letters/071204-correlogic.html.  Accessed on February 26, 2007.
   

Web Sites for Additional Information

1. American Cancer Society. Overview: Ovarian cancer.  Available at: http://www.cancer.org/docroot/CRI/CRI_2_1x.asp?rnav=criov&dt=33.  Accessed on February 26, 2007.
2. National Library of Medicine. Medical Encyclopedia: Ovarian Cancer.  Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000889.htm.  Accessed on February 26, 2007.
3. U.S. Department of Health and Human Services. National Cancer Institute.  Questions and Answers: OvaCheck and NCI/FDA Ovarian Cancer Clinical Trials Using Proteomic Technology.  Available at: http://home.ccr.cancer.gov/ncifdaproteomics/pdf/OvaCheckQandA.pdf.  Accessed on February 26, 2007.
   

Index

OvaCheck®
Proteomic Patterns in Serum for Screening and Detection of Ovarian Cancer
Serum-Based Diagnostic Test for Ovarian Cancer

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Policy History

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by an means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

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