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MP 2.04.54

Microarray-based Gene Expression Testing for Cancers of Unknown Primary


Medical Policy    
Section
Medicine
 
Original Policy Date
12/11/08
Last Review Status/Date
Reviewed with literature search/11:2012
Issue
11:2012
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

Cancers of unknown primary (CUP) represent 3% of all cancer cases in the U.S. A detailed history and physical, as well as radiologic and histologic testing, can identify some but not all primary sources of secondary tumor. It is suggested that identifying a likely primary source with microarray-based gene expression testing and directing treatment accordingly may improve health outcomes.

Cancers of Unknown Primary

Cancers of unknown primary (CUP), or occult primary malignancies, are tumors that have metastasized from an unknown primary source; they make up approximately 3% of all cancer cases in the U.S. Identifying the primary origin of a tumor can dictate cancer-specific treatment, expected outcome, and prognosis. (1)

Most cancers of unknown primary are adenocarcinomas or undifferentiated tumors; less commonly, they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteo- and chondrosarcomas rarely produce cancers of unknown primary. The most common primary sites of cancers of unknown primary are lung and pancreas, followed by colon and stomach, then breast, ovary, prostate, and solid-organ carcinomas of the kidney, thyroid, and liver. Conventional methods used to aid in the identification of the origin of a CUP include a thorough history and physical examination; computed tomography (CT) scans of the chest, abdomen, and pelvis; routine laboratory studies; and targeted evaluation of specific signs and symptoms. (2)

Biopsy of a CUP with detailed pathology evaluation may include immunohistochemical (IHC) analysis of the tumor. IHC identifies different antigens present on different types of tumors and can usually distinguish an epithelial tumor (i.e., carcinoma) from a melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of a carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. The results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.

The current success rate of the diagnostic workup of a CUP is 20–30%, including consideration of clinical, radiologic, and extensive histopathologic methods. (3) Recent advances in the understanding of gene expression in normal and malignant cells have led researchers to explore molecular classification as a way to improve the identification of the site of origin of a cancer of unknown primary.

Molecular Classification of Cancers

The molecular classification of cancers is based on the premise that, despite different degrees of loss of differentiation, tumors retain sufficient gene expression “signatures” as to their cell of origin, even after metastasis. Theoretically, it is possible to build a gene expression database spanning many different tumor types to compare to the expression profile of very poorly differentiated tumors or a cancer of unknown primary to aid in the identification of the tumor type and organ of origin. The feasibility of using molecular classification schemes with gene expression profiling (GEP) to classify these tumors of uncertain origin has been demonstrated in several studies. (4-7)

Ramaswamy and colleagues, using microarray gene expression analysis of more than 16,000 genes, showed 78% classification accuracy of 14 common tumor types. (5) Su and colleagues, using large-scale RNA profiling with microarrays, accurately predicted the anatomical site of tumor origin for 90% of 175 carcinomas. (6) Bloom et al. combined multiple tumor microarray databases, creating a large collection of tumors, including 21 types, resulting in a molecular classification scheme that reached 85% accuracy. (8) Although microarray technology enables large numbers of genes to be evaluated at the same time, it is complex and time-consuming and is limited in its use as mostly a research tool. (4) In addition, since formalin fixation can degrade RNA, fresh/frozen tissue is preferred for better accuracy with microarray technology; however, formalin-fixed is the standard for pathology material in current practice. (9)

One such microarray technology is the Pathwork® Pathchip. The test measures the expression of more than 1,500 genes and compares the similarity of the GEP of a CUP to a database of known profiles from 15 tissues with more than 60 histologic morphologies. The report generated for each tumor consists of a “similarity score,” which is a measure of similarity of the GEP of the specimen to the profile of the 15 known tumors in the database. Scores range from 0 (very low similarity) to 100 (very high similarity), and sum to 100 across all 15 tissues on the panel. If a single similarity score is greater than or equal to 30, it indicates that this is likely the tissue of origin. If every similarity score is between 5 and 30, the test result is considered indeterminate, and a similarity score of less than 5 rules out that tissue type as the likely origin.

MiRview mets® (Rosetta Genomics, Philadelphia, PA) is another microarray technology which uses microRNAs (miRNA), small non-coding, single-stranded RNA molecules that regulate genes post-transcription, as a signature for tumor differentiation. The expression levels of these miRNAs have been shown to be a sensitive biomarker across various pathologic conditions. Samples for this test are formalin-fixed paraffin-embedded (FFPE) tissue. The MiRview test utilizes 48 panel markers used to detect 22 tumor types in a known database of 336 tumors with a range of 1 to 49 tumors per type. The results from the test provide a tumor of origin but may list multiple possibilities calculated by a binary decision tree and K nearest neighbor algorithm. A second generation test, miRview® mets2, has recently been developed, which expands the number of tumor types to 42 primary origins with a panel of 64 miRNAs.

An alternative method to measure gene expression is real-time quantitative polymerase chain reaction (RT-PCR). RT-PCR can be used at the practice level; however, it can only measure, at most, a few hundred genes, limiting tumor categorization to 7 or fewer types. Tumor classification accuracy rates using RT-PCR have been reported to be as high as 87%, but less so (71%) the more undifferentiated the tumor tested. (4) One assay that uses qRT-PCR is the CancerTypeID® (CancerTypeID; bioTheranostics, Inc., San Diego, CA) assay, which measures the expression of messenger RNA in a CUP tissue sample. Samples for this are FFPE tissue sections or unstained 10 micron sections on glass slides. The expression levels of 92 genes (87-tumor associated genes and 5 reference genes for normalization) are used to detect 27 tumor types in a known database of 578 tumors with a range of 5 to 49 tumors per type. The report generated is the probability for the main cancer type, possible subtypes, tumor types not able to be excluded, and those ruled out with 95% confidence calculated by K nearest neighbor analysis.

Regulatory Status

In July 2008, test “Pathwork® Tissue of Origin” (Pathwork Diagnostics, Inc., Sunnyvale, CA) was cleared with limitations* for marketing by the U.S Food and Drug Administration (FDA) through the 510(k) process. The FDA determined that the test was substantially equivalent to existing tests for use in measuring the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated, and metastatic cases) that were diagnosed according to current clinical and pathologic practice. The database contains examples of RNA expression patterns for 15 common malignant tumor types: bladder, breast, colorectal, gastric, hepatocellular, kidney, non-small cell lung, ovarian, pancreatic, prostate, and thyroid carcinomas, melanoma, testicular germ cell tumor, non-Hodgkin’s lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient's clinical history and other diagnostic tests evaluated by a qualified clinician.

*Limitations to the clearance were as follows:

The Pathwork® Tissue of Origin Test is not intended to establish the origin of tumors that cannot be diagnosed according to current clinical and pathologic practice, (e.g., carcinoma of unknown primary). It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathologic practice, nor to predict disease course, or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork® Tissue of Origin Test database may have RNA expression patterns that are similar to RNA expression patterns in tumor types in the database, leading to indeterminate results or misclassifications.

In June 2010, the “Pathwork® Tissue of Origin Test Kit-FFPE” (Pathwork Diagnostics) was cleared for marketing by the FDA through the 510(k) process. The 2010 clearance is an expanded application, which allows the test to be run on a patient’s formalin-fixed, paraffin-embedded (FFPE) tumor and has the same indications and limitations. In May 2012, minor modifications to the “Pathwork® Tissue of Origin Test Kit-FFPE” were determined to be substantially equivalent to the previously approved device by the U.S. Food and Drug Administration (FDA) through the 510(k) process.

Both CancerTypeID® and miRview® have not submitted their test for FDA approval. 


Policy

Gene expression profiling is considered investigational to evaluate the site of origin of a tumor of unknown primary, or to distinguish a primary from a metastatic tumor. 


Policy Guidelines

Effective in July 2013, there is a specific CPT coding for the Pathwork Tissue of Origin test:

81504 - Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores

Prior to July 2013, the preparation of the probes might have been coded using a combination of the molecular diagnostic codes 83890-83913 and the analysis of the probes might have been coded using array-based evaluation of multiple molecular probes codes 88384-88386 based on the number of probes analyzed.

Prior to July 2013, Pathwork Diagnostics stated that they used 84999 (unlisted chemistry procedure).


Benefit Application

BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.


Rationale 

Pathwork® Tissue of Origin Test

Analytic Validity (technical performance, i.e., reproducibility)

Fresh frozen tumor sample

In 2008, Dumur and colleagues analyzed performance characteristics of the Pathwork® test in a cross-laboratory comparison study of 60 poorly and undifferentiated metastatic (77%) and primary (23%) tumors. (10) Three academic and one commercial laboratory received archived frozen tissue specimens for procurement and processing at their individual sites. Steps performed by each of the 4 laboratories included tissue handling, RNA extraction, and microarray-based gene expression assays using standard microarray protocol. The resulting microarray data generated at each laboratory were sent in a blinded fashion to Pathwork Diagnostics for generation of similarity scores for each type. Reports of the similarity scores were sent back (blinded) to the pathologists at the 4 laboratories for their use in generating an interpretation. Data were compared among the 4 laboratories to determine assay reproducibility. Correlation coefficients were between 0.95 and 0.97 for pathologists’ interpretations of the similarity scores, and cross-laboratory comparisons showed an average 93.8% overall concordance between laboratories in terms of final tissue diagnosis.

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

Analytical performance characteristics of the Pathwork® test for FFPE were analyzed in a cross-laboratory comparison study of 60 poorly and undifferentiated metastatic (45%) and primary (35%) tumors. Each of the 15 tumor tissue types were represented by 4 specimens each, with the exception of breast (n=3) and soft tissue sarcoma (n=5). Samples were distributed among 3 laboratories for procurement and processing at their individual sites. Data were compared among the 3 laboratories to determine assay reproducibility. Correlation coefficients were between 0.92 and 0.93 for pathologists’ interpretations of the similarity scores, and cross-laboratory comparisons showed an average 82.1% overall concordance between laboratories in terms of final tissue diagnosis. A detailed summary of the data is available online at: http://www.accessdata.fda.gov/cdrh_docs/reviews/K080896.pdf. Additional analyses of the analytic performance of the test have produced similar results. (11, 12)

Clinical Validity (sensitivity and specificity)

Fresh frozen tumor sample

The clinical validation study for the Pathwork® Tissue of Origin test that was submitted to the U.S. Food and Drug Administration (FDA) involved a comparison of the gene expression profiles of 25 to 69 samples to each of the 15 known tumors on the Pathwork® panel (average 36 specimens per known tumor). The specimens included poorly differentiated, undifferentiated, and metastatic tumors. A similarity score was given to 545 specimens and then compared to the available specimen diagnosis. Based on the 545 results, the probability that a true tissue of origin call was obtained when a similarity score of 30 or more was reported was 92.9% (95% confidence interval [CI]: 90.3–95.0%), and the probability that a true-negative tissue call was made when a similarity score of 5 or less was reported was 99.7% (95% CI: 99.6–99.8%). Overall, the Pathwork® performance comparing the profiles of the 545 specimens to the panel of 15 known tumor types showed a positive percent agreement of 89.4% (95% CI: 86.5-91.8%), negative percent agreement of 99.6% (95% CI: 98.6–100%], non-agreement of 6.2% (95% CI: 4.4–8.6%), and indeterminate of 4.4% (95% CI: 2.8–6.5%).

Monzon and colleagues conducted a multicenter blinded validation study of the Pathwork® test. (13) The specimens included poorly differentiated, undifferentiated, and metastatic tumors. A total of 351 frozen specimens and electronic files of microarray data on 271 specimens were obtained, with 547 meeting all inclusion criteria. A similarity score was given to the specimens, which was then compared to the original pathology report that accompanied the specimen. Overall, the Pathwork® performance comparing the profiles of the 547 specimens to the panel of 15 known tumor types showed an overall agreement of 87.8% (95% CI: 84.7–90.4%) with the reference diagnosis. Sensitivity and specificity were 87.8% (95% CI: 84.7–90.4%) and 99.4% (95% CI: 98.3–99.9%), respectively, with the original pathology report acting as the reference standard. The authors acknowledged that since there was no independent confirmation of the original pathology, using the pathology reports as the reference standard could introduce errors into the study results. Agreement differed by site: 94.1% for breast, 72% for both gastric and pancreatic. Performance differences between tissue sites were statistically different (chi-squared=42.02; p=0.04; degrees of freedom [df]=28; n=547). Rates of agreement between test result and reference diagnosis varied by site: 88%, 84.4%, 92.3%, and 89.7% for Clinical Genomics facility, Cogenics, Mayo Clinic, and the International Genomics Consortium, respectively, but these differences were not statistically significant.

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

The clinical validation study for the Pathwork® Tissue of Origin test Kit-FFPE that was submitted to the U.S. Food and Drug Administration (FDA) involved a comparison of the gene expression profiles of 25 to 57 samples to each of the 15 known tumors on the Pathwork® panel (average 31 specimens per known tumor). The specimens included poorly differentiated, undifferentiated, and metastatic tumors. A similarity score was given to 462 specimens and then compared to the available specimen diagnosis. Based on the 462 results, the probability that a true tissue of origin call was obtained when a similarity score was reported was 88.5% (95% CI: 85.3-91.3%), and the probability that a true-negative tissue call was made when a similarity score of 5 or less was reported was 99.8% (95% CI: 99.7–99.9%). Overall, the Pathwork® performance comparing the profiles of the 462 specimens to the panel of 15 known tumor types showed a positive percent agreement of 88.5% (95% CI: 85.3-91.3%), negative percent agreement of 99.1% (95% CI: 97.6–99.7%], non-agreement of 11.5% (95% CI: 8.7–14.7%). Further details of these data are available online at: http://www.accessdata.fda.gov/cdrh_docs/reviews/K080896.pdf.

Clinical Utility (impact on patient outcomes)

Two clinical trials are currently recruiting patients to test the direct clinical utility and the clinical application of gene expression profiling (GEP) to patient management and tumor site-specific therapy of the Pathwork ® Tissue of Origin test. See the clinical trials summary below for further information.

CancerTypeID®

Analytic Validity (technical performance, i.e., reproducibility)

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

Erlander and colleagues analyzed the analytic performance characteristics of the 92-gene CancerTypeID test (bioTheranostics, San Diego, CA). (14) A training set of 2,557 tumor samples was created from multiple tumor banks and commercial sources with 2,206 samples included in the final internal validation dataset. These samples expanded on the standard CancerTypeID algorithm to increase tumor coverage and depth across 30 main cancer types and 54 histologic sub-types. Reproducibility was calculated from the observed cycle time for the 92 genes and 5 normalization genes using positive and negative controls. A total of 194 independent runs that included 4 operators provided the overall mean percentage coefficient of variation (CV) for the positive controls, which were 1.69% and 2.19% for the 92-genes and 5 normalization genes, respectively; for the negative controls the CV was 1.25% and 1.66% for the 92-genes and 5 normalization genes, respectively.

Clinical Validity (sensitivity and specificity)

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

A multi-center study of the 92-gene CancerTypeID® was undertaken to assess the test’s clinical validity by Kerr and colleagues. (15) FFPE specimens for this study were from approximately 50% metastatic tumors of any grade with the remainder poorly differentiated primary tumors collected within 6 years from the time of testing. Laboratory personnel at 3 study sites, blinded to all information except biopsy site and patient gender, performed diagnostic adjudication on the 1,017 cases selected for inclusion. Adjudication failed on 60 cases and another 167 were excluded per protocol or due to quality control reasons. A total of 790 cases, across 28-tumor types, were classified according to class or main type and subtype with the 92-gene assay. Similarity score of ≥85% was specified a priori as a threshold for classification with cases falling below this value determined to be unclassifiable by the test. When the results of the 92-gene test were compared with the adjudicated diagnosis the overall sensitivity of the 92-gene assay was 87% (95% CI: 84-89%) with a range of 48% to 100% within tumor types. In addition, the reference diagnosis was incorrectly ruled out in 5% of cases while 5.9% remained unclassifiable. The test specificity was uniformly high in all tumor types, ranging from 98% to 100%. Positive predictive values were greater than 90% in 16 of 28 tumor types, with an overall range of 61% to 100%. In an ANCOVA sub-group analysis, assay performance was found to be unaffected by tumor type (metastatic or primary), histologic grade, or specimen type affected assay performance.

The clinical performance characteristics of the 92-gene CancerTypeID test were investigated by Erlander and Colleagues. (14) A training set of 2,557 tumor samples was created from multiple tumor banks and commercial sources. After exclusion of samples for inadequate tumor content, inconsistent or inconclusive pathologic information, cycle time >28 or independent pathologic review, 2,206 samples were included in the final internal validation dataset. These samples all underwent qRT-PCR with the 92-gene assay primer-probe design to serve as inputs for a modification to the standard CancerTYPEID classification algorithm. Overall sensitivity of the CancerTypeID test determined by cross validation was 87% (95% CI: 85-88%) for main tumor type with a specificity of 100% (95% CI: 99-100%). The positive predictive value for main type accuracy was 87% and the negative predictive value was 100%. For tumor subtypes these values were similar with a sensitivity of 85% (95%: 83-86%), specificity of 100 (95% CI: 100-100%), positive predictive value of 85% and negative predictive value of 100%. One-hundred eighty-seven independently collected tissue samples with specimens derived from formalin-fixed, paraffin-embedded blocks (84%) and snap-frozen tissues (16%) were also used to test the performance of the new algorithm. This test set included 28 of the 30 main cancer types and had an overall sensitivity of 83%, with individual classes ranging from 50% to 100%.

Clinical Utility (impact on patient outcomes)

Hainsworth and colleagues conducted a multi-site prospective case-series of the 92-gene CancerTypeID® assay. (16) The FFPE biopsy specimen for this study included adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or squamous carcinoma. A total of 289 patients were enrolled for this study, and 252 had adequate biopsy tissue for the assay. The molecular profiling assay predicted a tissue of origin in 247 (98%) of 252 patients. One-hundred nineteen assay predictions were made with ≥80% similarity score and the rest were below 80% probability. Twenty-nine patients did not remain on study due to decreasing performance, brain metastases, or patient and physician decision. Of the remaining 223 patients, 194 (87%) received assay-directed chemotherapy, and 29 received standard empiric therapy. The median overall survival of the 194 patients receiving assay-directed chemotherapy was12.5 months, which was found to be within the a priori-specified improvement target of 30% compared with historical trial data on 396 performance-matched CUP patients receiving standard empiric therapy at the same center.

miRview® mets2

Analytic Validity (technical performance, i.e., reproducibility)

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

One study by Chajut et al. provided information on the analytic validity of the miRview® mets2 test. The specimens for this study were 174 FFPE samples, which were independently tested by Rosetta Genomics research and development laboratory and a CLIA-approved clinical laboratory to determine concordance of the miRNA profiles. Inter-laboratory concordance was found to be greater than 95% in 160 of 174 samples. (17)

Clinical Validity (sensitivity and specificity)

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

The clinical validity of the miRview® mets2 test was assessed by Meiri et al. in a sample of 509 FFPE specimens. (18) Four-hundred eighty-nine of these samples were successfully processed, and the results were compared to the known origin of the specimen. The sensitivity of the test was 85.6%, with a specificity of greater than 99%. Three smaller clinical validity studies testing between 83 and 204 samples reported similar sensitivity and specificity, ranging from 84.3% to 86% and 95% to 99% respectively. (19-21)

Clinical Utility (impact on patient outcomes)

No published data on the clinical utility of miRview® mets2 and impact on patient treatment decision or diagnosis has been identified in the literature.

Other Microassay Tests for CUP

Clinical Validity (sensitivity and specificity)

Formalin-fixed, paraffin-embedded (FFPE) tumor sample

Other studies have analyzed the clinical validity of using microarray gene expression technology. One study used microarray technology (CupPrint, Agendia, Amsterdam, the Netherlands), that used FFPE tumor samples. The CupPrint assay utilizes the same internal validation data set as the CancerTypeID® test and as is currently marketed outside of the United States. The study analyzed 495 genes in 84 patients with tumors of known origin and 38 patients with cancer of unknown primary (CUP) to assess the potential contribution to patient management. (3) Sixteen of the patients with CUP had their primary site of tumor origin identified by standard laboratory techniques. Molecular testing identified the correct site of tumor origin in 94% of cases of CUP and 83% of the tumors of known origin.

Clinical Utility (impact on patient outcomes)

One small study using microarray technology (not Pathwork®) on FFPE tumor retrospectively analyzed the GEP of tumors from 21 patients with CUP. The clinical relevance and implications of the results on patient management were reviewed. (22) In the 21 patients, standard methods had failed to determine a primary tumor origin. Results of GEP were reviewed in the context of tumor histology and clinical suspicion of tumor origin. Gene expression profiling confirmed the clinical suspicion in 16 of 21 cases, with a clinical/GEP inconsistency in 4 of 21 and a pathologic/gene profile inconsistency in 1 patient. The authors concluded that the use of GEP would have influenced patient management in 12 of 21 of the cases.

Ferracin and colleagues published a report of MicroRNA profiling using 101 FFPE tumor samples from primary cancers and metastases. (23) Forty samples, of 10 cancer types, were used to build a cancer-type-specific microRNA signature. This signature was then used to predict the primary site of metastatic cancer. Overall accuracy was 100% for primary cancers and 78% for metastatic cancers in the cohort sample. The signature was then applied to a published set of 170 samples where the prediction rates were consistent with the cohort results.

Summary

The available literature suggests that microarray-based gene expression testing may result in a high accuracy rate of identifying cancers of unknown primary when comparing the results to a known tissue of origin. However, without data on how these tests would alter clinical practice and clinical health outcomes (clinical utility), the investigational policy statement remains unchanged. A trial where patients with a cancer of unknown primary were randomized to receive treatment based on the results of these types of tests or based on standard diagnostic procedures would be useful to determine the clinical utility of gene-expression testing of cancers of unknown primary.

Clinical Trials

An October 2012 search of the National Cancer Institute and online Clinicaltrials.gov databases returned 2 clinical trials currently recruiting patients to test the direct clinical utility and the clinical application of gene expression profiling (GEP) to patient management and tumor site-specific therapy of the Pathwork® Tissue of Origin test. One randomized European Phase 3 trial, NCT01540058, began in March 2012 with a completion date of October 2016. A treatment strategy guided by Pathwork® Tissue of Unknown Origin analysis followed by treatment for the suspected primary cancer is compared to an empiric strategy in patients with CUP. The study’s primary outcome is progression from date of randomization and will also collect tumor response rate, toxicity, and overall survival. An observational prospective case series in the United States, NCT0649453, began May 2012 with a completion date of May 2015. This study aims to assess the cancer-specific clinical decisions before and after receipt of results from the Pathwork® Tissue of Origin test with an outcome of 2-year survival. One clinical trial of miRview® mets was completed in April 2012, NCT01202786, in Israel. The trial investigated the cost-effectiveness of using the miRview test compared to conventional workup of patients with cancer of unknown primary origin. Sixty participants were enrolled, and the following data were collected: cost and time of the diagnostic process from day 1 of the study to the decision on treatment program, the concordance between the miRview result compared with standard workup, treatment response, and overall survival.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network guidelines for the workup of an occult primary malignancy address the use of molecular methods in the classification of tumors. They conclude that there are insufficient data to confirm whether gene expression profiling can be used in choosing treatment options that would improve the prognosis of patients with occult primary cancers. Therefore, the panel does not recommend the testing as a part of routine evaluation of a cancer of unknown primary origin.(24)

Medicare National Coverage

In 2011, Palmetto GBA, the Medicare contractor in California, issued positive coverage for the Pathwork® Tissue of Unknown Origin test. Because all tests are processed out of the Pathwork Diagnostics Laboratory in California, the test will be covered for Medicare patients in the United States. The test is currently the only Medicare-covered molecular diagnostic for identification of tissue of origin in patients with an unknown primary cancer.

References:

 

 

  1. National Cancer Institute. U.S. National Institutes of Health. Physician data query (PDQ). Carcinoma of unknown primary (PDQ®): treatment [2011 Update]. 2011. Available online at: http://www.cancer.gov/cancertopics/pdq/treatment/unknownprimary/healthprofessional. Last accessed October 2011.
  2. Oien KA, Evans TR. Raising the profile of cancer of unknown primary. J Clin Oncol 2008; 26(27):4373-5.
  3. Horlings HM, van Laar RK, Kerst JM et al. Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 2008; 26(27):4435-41.
  4. Ma XJ, Patel R, Wang X et al. Molecular classification of human cancers using a 92-gene real-time quantitative polymerase chain reaction assay. Arch Pathol Lab Med 2006; 130(4):465-73.
  5. Ramaswamy S, Tamayo P, Rifkin R et al. Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci USA 2001; 98(26):15149-54.
  6. Su AI, Welsh JB, Sapinoso LM et al. Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001; 61(20):7388-93.
  7. Tothill RW, Kowalczyk A, Rischin D et al. An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 2005; 65(10):4031-40.
  8. Bloom G, Yang IV, Boulware D et al. Multi-platform, multi-site, microarray-based human tumor classification. Am J Pathol 2004; 164(1):9-16.
  9. Talantov D, Baden J, Jatkoe T et al. A quantitative reverse transcriptase-polymerase chain reaction assay to identify metastatic carcinoma tissue of origin. J Mol Diagn 2006; 8(3):320-9.
  10. Dumur CI, Lyons-Weiler M, Sciulli C et al. Interlaboratory performance of a microarray-based gene expression test to determine tissue of origin in poorly differentiated and undifferentiated cancers. J Mol Diagn 2008; 10(1):67-77.
  11. Grenert JP, Smith A, Ruan W et al. Gene expression profiling from formalin-fixed, paraffin-embedded tissue for tumor diagnosis. Clin Chim Acta 2011; 412(15-16):1462-4.
  12. Pillai R, Deeter R, Rigl CT et al. Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimens. J Mol Diagn 2011; 13(1):48-56.
  13. Monzon FA, Lyons-Weiler M, Buturovic LJ et al. Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 2009; 27(15):2503-8.
  14. Erlander MG, Ma XJ, Kesty NC et al. Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. J Mol Diagn 2011; 13(5):493-503.
  15. Kerr SE, Schnabel CA, Sullivan PS et al. Multisite validation study to determine performance characteristics of a 92-gene molecular cancer classifier. Clin Cancer Res 2012; 18(14):3952-60.
  16. Hainsworth JD, Rubin MS, Spigel DR et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon Research Institute. J Clin Oncol 2012 [Epub ahead of print].
  17. Chajut A, Rosenwald S, Edmonston TB et al. Development and validation of a second generation microRNA-based assay for diagnosing tumor tissue origin. AACR 2011.
  18. Meiri E, Mueller WC, Rosenwald S et al. A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist 2012; 17(6):801-12.
  19. Mueller WC, Spector Y, Edmonston TB et al. Accurate classification of metastatic brain tumors using a novel microRNA-based test. Oncologist 2011; 16(2):165-74.
  20. Rosenfeld N, Aharonov R, Meiri E et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 2008; 26(4):462-9.
  21. Rosenwald S, Gilad S, Benjamin S et al. Validation of a microRNA-based qRT-PCR test for accurate identification of tumor tissue origin. Mod Pathol 2010; 23(6):814-23.
  22. Bridgewater J, van Laar R, Floore A et al. Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer 2008; 98(8):1425-30.
  23. Ferracin M, Pedriali M, Veronese A et al. MicroRNA profiling for the identification of cancers with unknown primary tissue-of-origin. J Pathol 2011; 225(1):43-53.
  24. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Occult Primary Version 1.2013 [Updated]. 2012. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/occult.pdf. Last accessed October 2012.

 

Codes

Number

Description

CPT  81504 Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores
ICD-9 Diagnosis    Investigational for all codes
ICD-10-CM (effective 10/1/14)    Investigational for all relevant diagnoses  
   C79.9 Secondary malignant neoplasm of unspecified site  
   C80.0 Disseminated malignant neoplasm, unspecified  
  C80.1 Malignant (primary) neoplasm, unspecified  
ICD-10-PCS (effective 10/1/14)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. 
Type of Service  Pathology/Laboratory
Place of Service  Laboratory/Reference Laboratory 

 


Index

Pathwork Tissue of Unknown Origin


Policy History

Date Action Reason

12/11/08

Add to Medicine section

New Policy

12/03/09 Replace policy Policy updated with literature search; reference 12 added, reference 13 updated. No change to policy statement
11/11/10 Replace policy Policy updated with literature search; reference 12 added, reference 1 and 13 updated; new test for formalin-fixed paraffin-embedded (FFPE) specimens added as investigational, no change to existing policy statement
11/10/11 Replace policy Policy updated with literature search; references 11, 12 and 14 added. No change to policy statement.
11/08/12 Replace policy Policy updated with literature search; references 14- 21 added. Other tests commercially available besides Pathwork were added to the policy. Policy statement changed to be generalizable to gene expression profiling and not specific to the Pathwork test