Laboratory Section - Analysis of Proteomic Patterns in Serum to Identify Cancer

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

While 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 marker, 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. This type of proteomic profiling has also been referred to as a “protein fingerprint.”

There are potential applications for proteomics in a variety of malignancies (including breast and gastrointestinal), but the two most commonly mentioned are ovarian and prostate cancer.

Ovarian Cancer

Currently, there are no effective screening techniques 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 proposed clinical applications. The OvaCheck (Correlogic Systems) 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.

The OvaCheck will be offered exclusively at reference laboratories. Originally the manufacturer had assumed that the test would not be subject to FDA approval since the test is performed exclusively at one reference laboratory and testing materials do not cross state lines (i.e., a “home brew” test). However, the FDA has formally questioned this assumption, and the FDA regulatory status is under review.

Prostate Cancer

Serum measurement of prostate specific antigen (PSA) is an accepted screening method for prostate cancer. Serum PSA results below 2.5 ng/ml and above 10.0 ng/ml are most reliable in determining cancer risk. However, values falling within this range are nonspecific, and thus many patients undergo biopsy for benign disease. Proteomics has been proposed as a technique to further evaluate cancer risk in this diagnostic “gray” zone. However, there is no proteomic test for prostate cancer that is currently commercially available.

Policy/Criteria

Analysis of proteomic patterns in serum for screening and detection of cancer, including but not limited to ovarian, prostate, breast and gastrointestinal cancer, is considered investigational.

Scientific Background

Ovarian Cancer

While there has been considerable publicity regarding the potential role for proteomics for cancer screening and detection (2-5), 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. (6) 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 than 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. Patients without cancer were considered at high risk, due either to familial breast or cancer syndrome or positivity 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 (6) 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 molecules that constitute the diagnostic patterns would be expected to be entirely different.” (7) Other comments and correspondence in the literatures also question the statistical analysis used by Petricoin (8) and other technical issues. (9)

In February 2004, the Society of Gynecologic Oncologists released the following (10):

“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.”

An updated search of the literature through January 2009 based on the Medline database did not return any new clinical trial data that would alter the conclusions reached above. For example, Posadas and colleagues demonstrated that gefitinib inhibited the phosphorylation of epidermal growth factor receptor in epithelial ovarian cancer tumor cells, providing evidence of targeted therapy in a clinical setting.  However, this study did not compare the use of proteomics to determine therapy versus standard empirical therapy. ( 11)  A recent review article updated ongoing research related to early detection of ovarian cancer, including the use of proteomics. (12) Reymond provides an overview of some of the key challenges that must be addressed in evaluating this technology. (13)  In summary, proteomics in the detection and prognosis of ovarian cancer remains investigational.

Prostate Cancer

Regarding prostate cancer, studies have reported preliminary results.  For example, Ornstein and colleagues reported the results of serum proteomic profiling in 154 men with serum PSA ranging from 2.5 to 15.0 ng/ml. (14) A total of 63 samples (30 malignant, 33 benign) were used as the training set to identify a proteomic pattern that could distinguish benign from malignant disease. The results of the training set were then applied to the remaining 91 samples (i.e., the “testing” set) in a blinded fashion. In this testing set of 63 with negative biopsies and 28 with positive biopsies, there was 100% sensitivity and 67% specificity. These data imply that if the results of proteomic profiling were used to deselect patients for biopsy, 42 of 63 (67%) patients without prostate cancer could have avoided biopsy. The authors note that using a training set of only 63 samples may be inadequate, and that “before this new technology can be applied in clinical practice, much larger and diverse training and testing sets will be needed.”

Summary

In summary, there are inadequate data in the peer-reviewed literature to permit scientific conclusions concerning the analysis of proteomic patterns as a method to detect and monitor ovarian, prostate or other malignancies.

Updated literature reviews were conducted through January 2009.  No clinical studies were found that would alter the conclusions noted above.  There were no large population-based prospective clinical trials that demonstrated the impact on clinical outcomes for proteomic testing in the screening or detection of cancer.  A number of preliminary studies were noted describing the potential use of this technique in other malignancies including lung cancer ( 15-17 ), astrocytomas, ( 18), colorectal cancer ( 19-20), breast cancer (21) and head and neck cancer. ( 22)

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.34
2. Conrads TP, Veenstra TD. The utility of proteomic patterns for the diagnosis of cancer. Curr Drug Targets Immune Endocr Metabol Disord 2004; 4(1):41-50
3. Conrads TP, Fusaro VA, Ross S et al. High-resolution serum proteomic features for ovarian cancer detection. Endocr Relat Cancer 2004; 11(2):163-78
4. Posadas EM, Davidson B, Kohn EC. Proteomics and ovarian cancer: implications for diagnosis and treatment: a critical review of the recent literature. Curr Opin Oncol 2004; 16(5):478-84
5. Cristea IM, Gaskell SJ, Whetton AD. Proteomics techniques and their application to hematology. Blood 2004; 103(10):3624-34
6. Petricoin EF, Ardekani AM, Hitt BE et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359(9306):572-7
7. Questions and Answers:  The NCI/FDA Proteomics Research Program, Its Research, and Diagnostic Tests by Private Industry (e.g. OvaCheck™) www.cancer.gov/newscenter/pressreleases/ProteomicsOvarian(Verified  01/16/09)
8. Correspondence. Proteomic patterns in serum and identification of ovarian cancer. Lancet 2002;360(9327):169-71
9. Diamandis EP. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst 2004;96(5):353-6
10. Society of Gynceologic Oncologists, Chicago, Illinois, Press release. February 7, 2004  http://www.sgo.org/WorkArea/showcontent.aspx?id=954  (Verified 01/16/08)
11. Posadas EM, Liel MS, Kwitkowski V et al.  A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer. Cancer. 2007; 1;109(7):1323-30
12. Bast RC Jr, Brewer M, Zou C et al. Prevention and early detection of ovarian cancer: mission impossible? Recent Results Cancer Res 2007; 174:91-100
13. Reymond MA, Schlegel W. Proteomics in cancer. Adv Clin Chem 2007; 44:103-42
14. Ornstein DK, Rayford W, Fusaro VA et al. Serum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 ng/ml. J Urol 2004; 172(4 pt 1):1302-5
15. Yang SY, Xiao XY, Zhang WG et al. Application of serum SELDI proteomic patterns in diagnosis of lung cancer. BMC Cancer 2005; 5:83
16. Yanagisawa K, Tomida S, Shimada Y et al. A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer. J Natl Cancer Inst. 2006;99(11):858-67
17. Taguchi F, Solomon B, Gregorc V et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst. 2007;99(11):838-46
18. Li J, Zhuang Z, Okamoto H et al. Proteomic profiling distinguishes astrocytomas and identifies differential tumor markers. Neurology 2006;66 (5):733-6
19. Xu WH, Chen YD, Hu Y et al. Preoperatively molecular staging with CM10 ProteinChip and SELDI-TOF-MS for colorectal cancer. J Zhejiang Univ Sci B 2006;7(3):235-40
20. Leman ES, Schoen RE, Weissfeld JL et al. Initial analyses of colon cancer-specific antigen (CCSA)-3 and CCSA-4 as colorectal cancer-associated serum markers. Cancer Res 2007; 67(12):5600-5
21. Belluco C, Petricoin EF, Mammano E et al. Serum proteomic analysis identifies a highly sensitive and specific discriminatory pattern in stage 1 breast cancer. Ann Surg Oncol 2007;14(9):2470-6
22. Gourin CG, Xia ZS, Han Y et al. Serum protein profile analysis in patients with head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132(4):390-7

Cross References

None

Laboratory Section Table of Contents