Read Proteomic Pattern Analysis of Blood for the Early Detection of Ovarian Cancer (e.g., OvaCheckTM) text version

CIGNA HEALTHCARE COVERAGE POSITION

Subject Proteomic Pattern Analysis of

Blood for the Early Detection of Ovarian Cancer (e.g., OvaCheckTM)

Table of Contents Coverage Position............................................... 1 General Background ........................................... 1 Coding/Billing Information ................................... 4 References .......................................................... 4

Revised Date ............................. 9/15/2006 Original Effective Date ............. 9/15/2004 Coverage Position Number ............. 0171 Hyperlink to Related Coverage Positions BRCA1 and BRCA2 Genetic Testing for Susceptibility to Breast and Ovarian Cancer Prophylactic Oophorectomy with or without Hysterectomy Tumor Markers for Diagnosis and Management of Cancer Transvaginal Ultrasound for Ovarian and Endometrial Cancer Screening or Surveillance

INSTRUCTIONS FOR USE Coverage Positions are intended to supplement certain standard CIGNA HealthCare benefit plans. Please note, the terms of a participant's particular benefit plan document [Group Service Agreement (GSA), Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Positions are based. For example, a participant's benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Position. In the event of a conflict, a participant's benefit plan document always supercedes the information in the Coverage Positions. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable group benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Positions and; 4) the specific facts of the particular situation. Coverage Positions relate exclusively to the administration of health benefit plans. Coverage Positions are not recommendations for treatment and should never be used as treatment guidelines. ©2006 CIGNA Health Corporation

Coverage Position

CIGNA HealthCare does not cover proteomic pattern analysis testing (e.g., OvaCheck TM) for diagnosing or management of ovarian cancer because it is considered experimental, investigational or unproven.

General Background

An estimated 20,180 new ovarian cancers and 15,310 ovarian cancer deaths will occur in the United States in 2006 (American Cancer Society [ACS], 2006). Epithelial ovarian cancer is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women over age 65. Approximately 5-10% of ovarian cancers have genetic predisposition and three distinct hereditary patterns have been identified: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers. The most important known risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. The highest risk appears in women with two or more first-degree relatives with ovarian cancer. The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer. Because ovarian cancer is often asymptomatic in its early stages, most patients have advanced disease at the time of diagnosis. Partly as a result of this, yearly mortality in ovarian

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cancer is approximately 65% of the incidence rate (National Cancer Institute [NCI], 2005; National Comprehensive Cancer Network [NCCN], 2006). At the present time, there is no effective screening tool for ovarian cancer that can be used in the general population. Ovarian cancer is diagnosed using ultrasound, computed tomography (CT) scans, and magnetic resonance imaging (MRI). When a mass is found or cancer is suspected, then a surgical biopsy must be performed to confirm the diagnosis, the origin of the cancer and its stage. This information is then used to determine the course of treatment that will be recommended for each individual patient (ACS, 2005). The cancer antigen 125 (CA-125) in combination with ultrasound is being used for surveillance of women at high-risk for ovarian cancer, as a treatment response indicator and to monitor the detection of recurrent disease. The disadvantages of using the CA-125 biomarker as a stand-alone screening tool are: its levels are nonspecific and can be elevated due to other non-cancerous conditions; only 50-60% of women diagnosed with stage I ovarian cancer have demonstrated an elevation in this biomarker; research has shown that it has a positive predictive value of 10%, but when used in combination with ultrasound, its positive-predictive value increases to 20% (NCI, 2005). In an effort to develop a screening tool that can detect ovarian cancer in its earliest stages rendering it amenable to curative measures, new research in the areas of proteomics and genomics has occurred. Proteomics is the systematic study of proteins in a particular cell, tissue, or organism. This term was first coined in 1994. Researchers are currently applying proteomic technology in studies for the early detection of and ongoing surveillance of cancer. There are millions of proteins within the human cell, and only a small percentage of these have been identified. Through genomics research it has been determined that the human genome is estimated to contain about 30,000 genes. The difference between the genome and the proteome is that the genome is static; it doesn't change from day to day. A protein or proteome undergoes constant change in response to the chemicals that surround it, and the cell type in which it is located; its concentration varies according to its location (e.g., cellular versus serum), and it can vary according to different disease states (NCI, 2005). The application of proteomic technologies is currently limited to research purposes (Posadas, 2005). U.S. Food and Drug Administration (FDA) Correlogics Systems, Inc. (Bethesda, MD) has developed a serum-based test (OvaCheckTM) for the early detection of protein expressions. According to the manufacturer, this test identifies proteins found in diluted denatured serum samples, and profiles their pattern based on their size and net electric charge by utilizing a mass spectrometer and electrospray ionization (ESI). Once the proteins are identified and profiled, they can be compared algorithmically to a database of normal cell protein profiles. Variances in size and/or net electric charges may be indicative of the development of ovarian cancer. Additional testing will be required to confirm the diagnosis. In 2004, the FDA informed Correlogic, Inc. that it did not plan to regulate activities of Correlogic and their partners, Quest and LabCorp, in their provision of OvaCheck. The FDA has recognized that there is sufficient regulatory oversight under their Clinical Laboratory Improvement Amendment (CLIA) of 1988. However, the FDA has informed Correlogic that the algorithmic software used to perform the analysis of this test is considered a medical device and, therefore, would fall under the FDA pre-market review jurisdiction. In August 2004, Correlogic Systems, Inc. decided to move the software program for its OvaCheck ovarian cancer-screening tool in-house as a result of the FDA pre-market determination (FDA, 2004). Literature Review In a Hayes Technology Assessment Brief published in April 2006, the authors concluded that due to the lack of published evidence, proteomic-based testing of serum is not recommended as a definitive or adjunct diagnostic tool for ovarian cancer. Clinical studies are needed to assess the accuracy of these tests, to compare them with currently used diagnostic tests and procedures, and to determine how they would affect patient morbidity and mortality rates. NCI is currently recruiting 400 women who will participate in a multi-institutional, observational study to develop a blood test that can be used to predict a relapse of ovarian, peritoneal, or fallopian tube cancer.

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The researchers hope to identify certain proteins that might represent a pattern, or "fingerprint," indicating increased risk of disease relapse (NCI, 2006). In 2005, the NCI clarified that the findings that have been discovered via the use of proteomic research are only the basis of an approach to the possible diagnosis of cancer. Prospective clinical trials that stringently test these hypotheses have been designed and will have to be completed prior to the development and marketing of a diagnostic test for the detection of cancer (NCI, 2005). The NCI has stated that for a disease such as ovarian cancer, which has an approximate prevalence of one out of every 2500 women in the general population, test results of 100% sensitivity and 99% specificity, would mean that there are 25 women falsely identified for every one true cancer found. This high false-positive rate calls for additional research and validation before it can be used as a screening tool (NCI, 2004). Petricoin et al. (2002) reported the results from a combined diagnostic study conducted by the NCI and the FDA. The proteomic patterns from a database were compared to the serum protein markers of 116 serum samples using matrix-assisted laser desorption ionization (MALDI). Fifty of these samples were from women with known ovarian cancer, and 50 samples were used as a control from women without ovarian cancer. The researchers also included 16 additional samples taken from women with various medical conditions whose status in relation to ovarian cancer was unknown. The serum samples were then compared to the algorithm database of proteomic patterns. Of the 50 cancerous samples, all were confirmed as cancerous by the algorithmic reading. The system also identified 16 samples as ovarian cancer stage I. Of the 66 non-cancerous samples, 63 were identified as cancer-free. This sample test produced results of 100% sensitivity and specificity of 95% with a positive predictive value of 94% (8499). The researchers concluded that these results justified the need for this type of testing to be conducted in a large population-based prospective study to validate their findings with patients with known cancer, suspected cancer, or as a basic population screening tool. During this study the algorithmic technology used to identify the samples was MALDI, whereas the technology used for review of the OvaCheck samples is electrospray ionization (ESI) type mass spectrometry. Due to the variance of systems that is used to process each type of serum sample, it is difficult to draw conclusions from this study regarding the clinical utility of this test. Professional Societies/Organizations The American College of Obstetrics and Gynecology (ACOG, 2004) supports the U.S. Preventive Services Task Force (USPST, 2004) recommendations concerning ovarian cancer screening. These recommendations indicate that there is no existing evidence that any screening test, including CA-125, ultrasound, or pelvic examination, reduces mortality from ovarian cancer. Furthermore, existing evidence that screening can detect early-stage ovarian cancer is insufficient to indicate that this earlier diagnosis will reduce mortality. In 2004, the Society of Gynecologic Oncologists (SGO) published their statement concerning the use of OvaCheck as a "serum-based diagnostic test for ovarian cancer and that additional research is needed to validate the test's effectiveness before it is offered to the public." The Committee on Gynecologic Practice and the Society of Gynecologic Oncologists (2003) indicated that although newer tumor markers and proteomics are undergoing investigation and appear promising, it is unclear whether they will help identify high-risk women or facilitate the early diagnosis of more women with ovarian cancer. Currently, there are no techniques that have proved to be effective in the routine screening of asymptomatic low-risk women for ovarian cancer. Summary At this time there is a lack of evidence through well-designed, large-population randomized, controlled clinical trials demonstrating the clinical utility of OvaCheckTM proteomic-based testing for the diagnosis, surveillance, or management of patient treatment protocols for ovarian cancer. Studies are needed to validate the sensitivity of this test in relation to patient outcomes, patient morbidity and mortality. Until these studies are conducted and published within the peer-reviewed literature, the role of OvaCheckTM in the screening, diagnosis and management of ovarian cancer remains unknown.

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Coding/Billing Information

Note: This list of codes may not be all-inclusive. Experimental/Investigational/Unproven/Not Covered: CPT* Codes HCPCS Codes ICD-9-CM Diagnosis Codes 183.0 183.8 Description No specific codes Description No specific codes Description Malignant neoplasm of ovary and other uterine adnexa Malignant neoplasm of ovary and other uterine adnexa, other specified sites of adnexa: Tubo-ovarian, Utero-ovarian, Malignant neoplasm of contiguous or overlapping sites of ovary and other uterine adnexa whose point of origin cannot be determined

*Current Procedural Terminology (CPT®) ©2005 American Medical Association: Chicago, IL.

References

1. American Cancer Society (ACS). Cancer facts & figures 2006. Updated 2006. Accessed Jul 2006. Available at URL address: http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf 2. American Cancer Society. How is ovarian cancer diagnosed? Revised May 2006. Accessed Jul 2006. Available at URL address: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_ovarian_cancer_diagnosed_33. asp 3. American College of Obstetricians and Gynecologists (ACOG). ACOG committee opinion: The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Number 280, December 2002. Int J Gynecol Obstet. 2003;80(2):235-8. 4. Andrews E. OvaCheck: breakthrough or also ran? Nat Rev of Med. 2004 Mar. Revised 2004. Accessed Aug 2005. Available at URL address: http://www.nationalreviewofmedicine.com/issue/2004_03_15/feature16_05.html 5. Breedlove G, Busenhart C. Screening and detection of ovarian cancer. J Midwifery Womens Health. 2005 Jan-Feb;50(1):51-4 6. Conrads TP, Fusaro VA, Ross S, Johann D, Rajapakse V, Hitt BA, et al. High-resolution serum proteomic features for ovarian cancer detection. Endocr Relat Cancer. 2004 Jun;11(2):163-78. 7. Correlogic Systems, Inc. Frequently asked questions. Revised 2005. Accessed Jul 2006. Available at URL address: http://www.correlogic.com/faqs.htm 8. Diamondis EP. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst. 2004;96(5:)353-6.

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9. Diamondis EP. Proteomic patterns in serum and identification of ovarian cancer. Lancet 2002;360:170. 10. HAYES alertTM. Major labs to offer new test for ovarian cancer. Lansdale, PA: HAYES, Inc.; ©2004 Winifred S. Hayes, Inc. February, 2004. 11. HAYES alert- Technology Assessment BriefTM. Proteomic-Based Testing (OvaCheckTM) for the detection of ovarian cancer. Lansdale, PA: HAYES, Inc.; ©2006 Winifred S. Hayes, Inc. April, 2006. 12. National Cancer Institute (NCI). Predictors of relapse of ovarian, peritoneal, and fallopian tube cancers. Updated Jun 2006. Accessed Jul 2006. Available at URL address: http://clinicaltrials.gov/ct/gui/show/NCT00086567;jsessionid=EBB38A08FB73550CBC8 13. National Cancer Institute (NCI). Proteomics. Revised 2004. Accessed Aug 2005. Available at URL address: http://www.cancer.gov/cancertopics/proteomics/print?page=&keyword 14. National Cancer Institute (NCI). The NCI/FDA Proteomics research program, its research, and diagnostic tests by Private Industry (e.g., OvaCheckTM): Questions and answers. Revised Sep 2005. Accessed Jul 2006. Available at URL address: http://www.cancer.gov/cancertopics/factsheet/ovacheckproteomicsqa/print?page=&keyword=. 15. National Cancer Institute (NCI). Questions and answers: Proteomics and cancer. Revised 2005. Accessed Jul 2006. Available at URL address: http://www.cancer.gov/cancertopics/factsheet/proteomicsqa/print?page=&keyword 16. Petricoin EF, Ardekani AM, Hitt BA, Levine PJ, Fusaro VA, Steinberg SM. Use of proteomic patterns in serum to identify ovarian cancer. Lancet. 2002 Feb 16;359(9306):572-7 17. Posadas EM, Simpkins F, Liotta LA, MacDonald C, Kohn EC. Proteomic analysis for the early detection and rational treatment of cancer-realistic hope? Ann of Oncol. 2005;16:16-22. 18. Screening for ovarian cancer: recommendation statement. U.S. Preventive Services Task Force. Am Fam Phy. 2005;71(4):759-62. 19. Society of Gynecologic Oncologists (SGO). Society of Gynecologic Oncologists statement regarding OvaCheckTM. Revised Feb 2004. Accessed Aug 2005. Available at URL address: http://www.sgo.org/images/pdfs/policy/OvaCheck_statement.pdf 20. U.S. Food and Drug Administration (FDA). Centers for Devices and Radiological Health: Office of in vitro diagnostic device evaluation and safety. Letter to Correlogic Systems, Inc. Revised Jul 2004. Accessed Jul 2006. Available at URL address: http://www.fda.gov/cdrh/oivd/letters/071204correlogic.html 21. U.S. Food and Drug Administration (FDA). Centers for Devices and Radiological Health: Office of in vitro diagnostic device evaluation and safety. Letter to Laboratory Corporation of America. Revised Mar 2004. Accessed Jul 2006. Available at URL address: http://www.fda.gov/cdrh/oivd/letters/030204-labcorp.html 22. U.S. Food and Drug Administration (FDA). Centers for Devices and Radiological Health: Office of in vitro diagnostic device evaluation and safety. Letter to Quest Diagnostics. Revised Mar 2004. Accessed Jul 2006. Available at URL address: http://www.fda.gov/cdrh/oivd/letters/030204quest.html 23. U.S. Food and Drug Administration (FDA). Devices and diagnostics letter online: Correlogic alters OvaCheck to avoid PMA submission. Revised Aug 2004. Accessed Jul 2006. Available at URL address: http://www.fdanews.com/ddl/31_31/fda/28068-1.html

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24. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality (AHRQ), Rockville, MD. Screening for ovarian cancer: brief evidence update. 2004 May. Accessed Jul 2006. Available at URL address: http://www.ahrq.gov/clinic/3rduspstf/ovariancan/ovcanup.htm 25. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality (AHRQ), Rockville, MD. Screening for ovarian cancer: recommendation statement. 2004 May. Accessed Jul 2006. Available at URL address: http://www.guideline.gov/summary/pdf.aspx?doc_id=4857&stat=1&string=screening+AND+ovaria n+AND+cancer

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