Medical Policy: 02.04.70
Original Effective Date: December 2017
Reviewed: December 2017
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Cancers of unknown primary (CUP) represents 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology (immunohistochemical (IHC) staining) can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment may improve health outcomes.
Cancers of unknown primary (CUP) or occult primary malignancies, are tumors that have metastasized from unknown primary source. Identifying the primary origin of a tumor can dictate cancer-specific treatment, expected outcome, and prognosis.
Most cancers of unknown primary (CUP) are adenocarcinoma or undifferentiated tumors (approximately 70%); less commonly, they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteosarcomas and chondrosarcomas rarely produce CUPs. The most common primary sites of CUPs are lung, pancreas, hepatobiliary tree and kidney, together accounting for approximately two-thirds of cases. Conventional methods used to aid in the identification of the origin of a CUP include a thorough history and physical examination, imaging to include computed tomography (CT) or positron emission tomography (PET), laboratory studies, tissue pathology (biopsy) and targeted evaluation of specific signs and symptoms.
Biopsy of a cancer of unknown primary (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 melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. Results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.
Recent advances in the understanding of gene expression in normal and malignant cells have led researchers to explore molecular classification to improve the identification of the site of origin of a CUP. 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 CUP to aid in the identification of 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.
Patients with cancer of unknown primary (CUP) have generally a poor prognoses. For example, patients with disease limited to lymph nodes have a median survival of 6 to 9 months, and those with disease that is extranodal 2 to 4 months. The premise of tissue of origin testing in CUPs is that identifying a likely primary tumor site will inform treatment selection leading to improved survival and other outcomes or as a predictive test. To evaluate whether treatment selection can be improved, the ability of test to suggest a likely site of origin (clinical validity) must first be shown. Demonstrating clinical validity may be problematic because patients with CUPs have not identified primary tumor for a reference standard. Imperfect reference standards must be relied on such as the available presumptive or a reference pathologic diagnosis, known tumor types, or comparisons IHC. A primary tumor diagnosed during follow-up might also be used as a reference standard, but its use would be subject to potential selection bias. Therefore, even substantial evidence supporting the ability of a test to suggest a likely site of origin will be insufficient to infer benefit. Convincing evidence for benefit requires demonstrating that using a test to select treatment will improve outcomes.
|Test||Manufacturer||Platform||Genes Assayed||Tumor Types Assessed|
|Tissue of Origin (TOO) (formerly known as the PathWork Tissue of Origin Test)||Cancer Genetics||Oligonucleotide microarray||2000||15|
|CancerTYPE ID||bioTheranostics||real time quantitative polymerase chain reaction||92||54|
|RosettaGX Cancer Origin||Rosetta Genomics||real time quantitative polymerase chain reaction(microRNA)||64||49|
Tissue of Origin (TOO) is a gene expression test that relies on genomic information to help identify origin in cases that are metastatic and/or poorly differentiated. Tissue of Origin (TOO) assesses 2,000 genes, covering 15 of the most common tumor types. These tumors include thyroid, breast, non-small cell lung, pancreas, gastric, colorectal, liver, bladder, kidney, non-Hodgkin’s lymphoma, melanoma, ovarian, sarcoma, testicular germ cell and prostate.
For each tumor specimen, the Tissue or Origin (TOO) test report provides Similarity Scores (SS) that are graphically represented. Similarity Score (SS) measures the similarity of the RNA expression pattern of the specimen to the RNA expression pattern of the indicated tissue. Similarity Score (SS) range from 0 (low) to 100 (high) and sum to 100 across all 15 tissues on the panel.
CancerTYPE ID is a molecular cancer classifier test that helps to identify the tumor type and subtype for cancers of unknown primary (CUP) or cancers with indeterminate, uncertain or differential diagnoses. The test uses real-time RT-PCR to measure the expression of 92 genes in the patient’s tumor and classifies the tumor by matching the gene expression pattern of the patient’s tumor to a database of known tumor types and subtypes, encompassing 50 tumor types.
The expression profile of 92 genes is obtained by extracting RNA from tumor-enriched sections of formalin-fixed paraffin embedded (FFPE) tissue and performing real-time quantitative RT-PCR using Taqman technology. This test identifies the most likely tissue origin and histological type based on the degree of similarity of the samples 92 gene expression profile to a reference database of gene expression profiles from tumors of known tissue origin and histological subtype. The probability is a measure of confidence for the classification, within the context of the reference database of over 2000 tumors. However, cancer types outside of these types may be indeterminate or potentially misclassified.
Cancer of unknown primary (CUP) cases can represent a clinical dilemma, without knowing the primary origin, it can be difficult to select the optimal therapy for patients. RosettaGX Cancer Origin is designed to help provide a diagnosis for such cases. RosettaGX Cancer Origin test uses custom designed microarray technology and can identify 49 cancer origins by measuring the expression level of 64 microRNAs.
The reported origin(s) are directly generated by algorithms (a binary decision tree classifier and KNN classifier) trained on data from 1300 known primary and metastatic tumors, with validated sensitivity of 85% or greater. MicroRNA extracted using organic solvents from formalin fixed paraffin embedded (FFPE) tissue microdissected (if necessary) to a tumor cell percentage of 60% or more. The relative expression of 64 microRNAs is quantified on a custom microarray, and their signals normalized to a reference set on the array, and entered into an algorithm that combines a binary decision tree and a k-nearest-neighbor classifier to determine tumor origin among 49 possible validated cancer origins. The result is reported as either a single tumor origin or as two possible origins listed in alphabetical order. If the probability for origin(s) is below a predetermined value, no result will be reported.
Based on review of the medical literature the evidence for analytic validity of the 3 commercially available tests Tissue of Origin (TOO) test (formerly known as the PathWork Tissue of Origin Test), CancerTYPE ID and RosettaGX Cancer Origin pertain primarily to assay reproducibility, quality control, detection limit, and specificity (effect of interfering substances). While some available evidence supports aspects of analytic validity tests, only the Tissue of Origin (TOO) Test has been cleared by the FDA.
Studies reported evidence that the Tissue of Origin Test can predict a likely site of origin using a variety of reference standards: reference or available diagnosis, a primary tumor identified during follow-up, and immunohistochemistry (IHC). Concordance rates in the range of 85% to 90% were reported compared with the reference standards employed.
The clinical validation study for the PathWork Tissue of Origin Test that was submitted to FDA in 2008 compared GEP tests for 25 to 69 samples with each of the 15 known tumors on the PathWork panel (mean, 36 specimens per known tumor). Specimens included poorly differentiated, undifferentiated, and metastatic tumors. A similarity score was assigned to 545 specimens and then compared with 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 93% (95% confidence interval [CI], 90% to 95%), and the probability that a true-negative tissue call was made when a similarity score of 5 or less was reported was 100% (95% CI, 100% to 100%). Overall PathWork performance comparing the profiles of the 545 specimens with the panel of 15 known tumor types showed a positive percent agreement of 90% (95% CI, 87% to 92%), negative percent agreement of 100% (95% CI, 99% to 100%), nonagreement of 6% (95% CI, 4% to 9%), and indeterminate of 4% (95% CI, 3% to 7%).
In 2009, Monzon et al conducted a multicenter blinded validation study of the PathWork test. 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 with the original pathology report that accompanied the specimen. The PathWork performance comparing the profiles of the 547 specimens with the panel of 15 known tumor types showed overall sensitivity (positive percent agreement with reference diagnosis) of 88% (95% CI, 85% to 90%) and overall specificity (negative percent agreement with reference diagnosis) of 99% (95% CI, 98% to 100%), with the original pathology report acting as the reference standard. The authors noted that because there was no independent confirmation of the original pathology, using the pathology reports as the reference standard could introduce error into study results. Agreement differed by cancer type: 94% for breast and 72% for both gastric and pancreatic; these differences were statistically significant (p=0.04). Agreement between test result and reference diagnosis varied by testing center: 88%, 84%, 92%, and 90% for Clinical Genomics facility, Cogenics, Mayo Clinic, and the International Genomics Consortium, respectively (differences not statistically significant).
In 2013, Azueta et al compared IHC in FFPE tissue and the PathWork test in archived fresh-frozen tissue in a series of 32 metastatic tumors of suspected gynecologic origin (25 metastatic to the ovary, 7 peritoneal metastases). The primary site of origin was determined by clinical follow-up in 29 (83%) patients and was considered the criterion standard. All peritoneal metastases originated from the ovary, and metastases to the ovary originated from the colon (11 cases), breast (5 cases), stomach (4 cases), endometrium (1 case), and an angiosarcoma (1 case). Eligible frozen sections from these cases and 3 with CUP were required to contain at least 60% tumor and less than 20% necrotic tissue. PathWork concordance was 86% (25/29 diagnoses); in 2 cases, diagnoses were incorrect, and 2 cases had 2 possible diagnoses. PathWork diagnosed 2 of 3 cases of unknown primary after clinical follow-up. IHC concordance was 79% (23/29 diagnoses); 4 cases were indeterminate, and 2 cases had 2 possible diagnoses; diagnoses of 2 of 3 cases of unknown primary after clinical follow-up matched the PathWork diagnoses.
The clinical validation study for the PathWork Tissue of Origin Test Kit-FFPE submitted to FDA in 2009 compared GEP results for 25 to 57 samples to each of the 15 known tumors on the PathWork panel (mean, 31 specimens per known tumor). Specimens included poorly differentiated, undifferentiated, and metastatic tumors. A similarity score was assigned to 462 specimens and then compared with 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 (positive percent agreement) was 89% (95% CI, 85% to 91%), and the probability that a true negative (ie, unknown) tissue call was made when a similarity score of 5 or less was reported (negative percent agreement) was 99% (95% CI, 98% to 100%). The proportion of nonagreement (false negatives) was 12% (95% CI, 9% to 15%). Further details of these data are available in FDA’s decision summary.
In 2013, Handorf et al reported on a clinical validation study of FFPE metastatic cancer specimens of known primary tumors representing the 15 tissue types on the PathWork test panel. PathWork’s diagnostic performance was compared with IHC in 160 tumor samples. Overall concordance with known diagnoses (ie, accuracy) was 89% for PathWork versus 83% for IHC (p=0.013). In 51 poorly differentiated and undifferentiated tumors, PathWork accuracy was 94% and IHC accuracy was 79% (p=0.016). In 106 well-differentiated and moderately differentiated tumors, PathWork and IHC performance was similar (87% and 85% accuracy, respectively; p=0.52). These results are based on 157 specimens for which both PathWork and IHC testing were performed; 3 specimens from the original set of 160 were considered nonevaluable by PathWork (similarity score, <20) and were excluded.
Results derived from 4 samples reported evidence for supporting the ability of CancerTYPE ID to predict a likely site of origin. Reference standards included a known tumor type, reference diagnosis, a primary tumor identified during follow-up, and IHC. Reported sensitivities varied according to tumor type generally ranged from 80% to over 90%.
Erlander et al (2011) revised the original classifier algorithm3 using 2206 samples created from multiple tumor banks and commercial sources. These samples expanded on the standard CancerTYPE ID algorithm to increase tumor coverage and depth across 30 main cancer types and 54 histologic subtypes. Sensitivity of the classifier for the main cancer type based on internal validation (leave-one-out cross validation) was 87% (95% CI, 85% to 88%) and, for the histologic subtype, 85% (95% CI, 83% to 86). In an independent test set of 187 samples, sensitivity was 83% (95% CI, 78% to 88%).
In 2012, Kerr et al reported on a multicenter study of the 92-gene CancerTYPE ID test conducted to assess the test’s clinical validity. Approximately half of FFPE specimens for this study were from metastatic tumors of any grade, and the remainder from poorly differentiated primary tumors processed within 6 years of testing. Laboratory personnel at 3 study sites, blinded to all information except biopsy site and patient sex, performed diagnostic adjudication on 790 tumors, across 28 tumor types. Each specimen was then classified according to class or main type and subtype with the 92-gene assay. A similarity score of 85% or greater was specified a priori as a threshold for classification, with cases falling below this value determined to be unclassifiable by the test. When results of the 92-gene test were compared with adjudicated diagnoses, overall sensitivity of the 92-gene assay was 87% (95% CI, 84% to 89%) with a range of 48% to 100% within tumor types. The reference diagnosis was incorrectly ruled out in 5% of cases and 6% remained unclassifiable. Test specificity was uniformly high in all tumor types, ranging from 98% to 100%. Positive predictive values ranged from 61% to 100% and exceeded 90% in 16 of 28 tumor types. In an analysis of covariance, assay performance was found to be unaffected by tissue type (ie, metastatic or primary), histologic grade, or specimen type. A 2014 sub-study of this dataset evaluated primary (41%) and metastatic (59%) tumors considered to have neuroendocrine differentiation (Merkel cell carcinoma, medullary thyroid carcinoma, pheochromocytoma, paraganglioma, pulmonary neuroendocrine carcinoma, pancreatic neuroendocrine carcinoma, gastrointestinal neuroendocrine carcinoma). For 75 included tumors, assay sensitivities were 99% (95% CI, 93% to 99%) for classification of neuroendocrine tumor type (eg, neuroendocrine, germ cell) and 95% (95% CI, 87% to 98%) for subtype (site of origin). Positive predictive values ranged from 83% to 100% for individual subtypes. A 2016 report by Brachtel et al examined a subset of samples from 109 patients with limited tissue studied by Kerr et al (2012) and 644 other consecutive cytology samples. In the 109 patients, sensitivity for tumor classification was 91% (95% CI, 84% to 95%) or consistent with the larger sample. From the 644 cases, a sensitivity of 87% (95% CI, 84% to 89%) was estimated.
In 2013, Greco et al published a retrospective, single-center study of 171 patients diagnosed with CUP after a clinical diagnostic workup (ie, before IHC). The purpose of the study was to evaluate the accuracy of GEP (CancerTYPE ID) by verifying results with latent primary tumor sites found months after initial presentation (24 patients) or with IHC and/or clinicopathologic findings (147 patients). Minimum test performance thresholds were prespecified. Tumor specimens adequate for GEP were obtained in 149 (87%) patients, and diagnoses were made in 144 (96%). Of 24 patients with latent primary tumor sites, CancerTYPE ID diagnoses were accurate in 18 (75%), and IHC diagnoses were accurate in 6 (25%). Of 52 patients with diagnosis made by IHC testing and subsequent GEP, diagnoses matched in 40 (77%). When IHC suggested 2 or 3 possible primary sites (97 patients), CancerTYPE ID diagnosis matched one of the proposed diagnoses in 43 (44%). Among 35 patients with discordant IHC and CancerTYPE ID diagnoses, clinicopathologic correlates and subsequent IHC supported the CancerTYPE ID diagnoses in 26 (74%). The authors concluded that GEP “complements standard pathologic evaluation” of CUP.
Consistent with other clinical validity data, Greco et al (2015) retrospectively reported on the use of CancerTYPE ID on archived samples from 30 patients with CUP and poorly differentiated neoplasms. This subset of patients with CUP is considered potentially treatment sensitive, but comprised a small number (4%) of the 751 CUP patients evaluated from 2000 through 2012 at Tennessee centers. A primary site was identified in 2 patients. A diagnosis was assigned by GEP in 25 (83%) of the samples. Although 7 recently evaluated patients received treatment based on the diagnosis provided, and 5 reportedly had "favorable" outcomes, whether benefit was obtained cannot be assessed.
In 2012, Meiri et al assessed the clinical validity of the miRview mets2 test in 509 FFPE specimens. Four hundred eighty-nine of these samples were successfully processed, and results were compared with the known origin of the specimen. Sensitivity of the test was 86%, and specificity exceeded 99%. Three smaller clinical validation studies testing 83 to 204 samples reported similar sensitivity and specificity, with ranges of 84% to 86% and 95% to 99%, respectively.
Using different reference standards, the tests have reported sensitivities or concordances generally high (e.g. 80% to 90% or more). However, clinical validity evidence does not provide support for potential benefit.
Nystrom et al (2012) enrolled 65 physicians (from 316 approached) caring for 107 patients with CUP in 2009 to participate in a study of management changes following a tissue of origin test. Prior to the test, physicians had no suspected diagnosis for 54 (41%) patients, which declined to 17 (16%) after testing. Changes in management were reported in 70 (65%) patients. Physicians reported test results were helpful with regard to diagnosis, choosing therapy, and triaging. Median survival was 14 months, which the authors suggest longer than 9 months for unselected chemotherapy treated CUP patients. However, the low physician participation rate and lack of a concurrent comparator group limits any implications of these results. The study was supported by PathWork Diagnostics and 2 authors company employees.
Yoon et al (2016) reported results of a multicenter phase 2 trial evaluating combined use of carboplatin, paclitaxel, and everolimus in patients with CUP. The primary outcome was objective response, and the study a 2-stage design with 11 or more responses in 50 assessable patients at the second stage considered success. There were 16 partial responses (objective response rate, 36%; 95% CI, 22% to 51%). Grade 3 or 4 adverse events occurred in 40 (87%) patients. Results from the PathWork Tissue of Origin Test were used post hoc to examine any association with response to therapy. In 38 of 46 patients, the test was successfully obtained and 10 different tissues of origin were predicted. In 19 patients with a tissue of origin where platinum/taxane therapy might be considered standard therapy, objective response rates were higher compared with other patients (53% vs 26%, p=0.097), accompanied by longer progression-free survival (PFS; 6.4 months vs 3.5 months, p=0.026; hazard ratio [HR], 0.47; 95% CI, 0.24 to 0.93), and longer OS (median, 17.8 months vs 8.3 months; p=0.005; HR=0.37; 95% CI, 0.18 to 0.76). The results suggested a tissue of origin test might identify platinum/taxane-sensitive tumors. However, the study was not designed to evaluate predictive use of the test, tissue of origin data were missing for 17% of patients, and severe adverse events were common.
From patients with CUP who had undergone a CancerTYPE ID assay between March 2008 and August 2009, Hainsworth et al (2012) identified those with a probable (≥80%) colorectal site of origin. A total of 125 patients (of 1544 results) were predicted to have a primary colorectal cancer (CRC). Physicians caring for patients were sent questionnaires with a request for deidentified pathology reports—42 (34%) responded (physicians were paid $250). The date of questionnaire mailing was not reported. A total of 32 patients were given CRC regimens (16 first-line therapy only, 8 first- and second-line therapy, 8 second-line therapy only) with a reported response rate of 50% following first-line and 50% following second-line therapy; 18 patients were given empiric CUP regimens with a response rate of 17%. For first-line therapies, physician-assessed PFS was longer following CRC regimens—8.5 months versus 6 months (p=0.11). The authors concluded that “Molecular tumor profiling seems to improve survival by allowing specific therapy in this patient subgroup” However, conclusions are limited by significant potential biases: low physician response rates and potential selection bias; unverified physician-reported retrospective assessment of progression, response, or death; absence of information on patient performance status to assess between-group prognostic differences; and the post hoc subgroup definition of uncertain generalizability to patients with CUP undergoing tissue of origin testing.
In 2013, Hainsworth et al published a multisite prospective case series of the 92-gene CancerTYPE ID assay. FFPE biopsy specimens for this study included adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or squamous carcinoma. A total of 289 patients were enrolled, and 252 (87%) 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 (48%) assay predictions were made with a similarity score of 80% or greater, and the rest were below 80% probability. Twenty-nine (12%) patients did not remain in the study due to decreasing performance status, brain metastases, or patient and physician decision. Of the remaining 223 patients, 194 (87%) received assay-directed chemotherapy and 29 (13%) received standard empiric therapy. Median overall survival of the 194 patients who received assay-directed chemotherapy (67% of the original patient sample) was 12.5 months, which exceeded a prespecified improvement threshold of 30% compared with historical trial data for 396 performance-matched CUP patients who received standard empiric therapy at the same center. Although these results are consistent with possible benefit from GEP testing in CUP, potential biases accompany the nonrandomized design—confounding variables, use of subsequent lines of empirical therapy, heterogeneity of unknown primary cancers, comparison with historical controls—and limit conclusions that can be drawn.
No published data on the clinical utility of RosettaGX Cancer Origin test and impact on patient treatment decision or diagnosis were identified in the literature.
There is limited indirect evidence from non-randomized studies for 2 of the tests concerning clinical utility and studies had significant limitations including comparisons with historical controls and possible selection bias. The absence of either convincing evidence from an unbiased nonrandomized study or randomized controlled trials prevents conclusions concerning clinical utility. Benefit would be most convincingly demonstrated through a marker strategy designated trial randomizing patients with cancers of unknown primary to receive treatment based on gene expression profiling results or usual care.
For individuals who have a cancer of unknown primary (CUP) who receive gene expression profiling, the evidence includes studies of analytic validity, clinical validity, and limited evidence on potential clinical utility. For the 3 commercially available tests reviewed Tissue of Origin (TOO) test (formerly known as the PathWork Tissue of Origin Test), CancerTYPE ID and RosettaGX Cancer Origin, there is some evidence to support relevant aspects of analytic validity; 1 test has been cleared by the Food and Drug Administration. Using different reference standards (known tumor type, reference diagnosis, a primary tumor identified during follow-up, immunohistochemical analysis) for the tissue of origin, the tests have reported sensitivities or concordances generally high (e.g. 80% to 90% or more). However, evidence for clinical validity does not support potential benefit. There is limited indirect evidence from nonrandomized studies on clinical utility, and all studies had significant limitations. Benefit would be most convincingly demonstrated through a marker strategy designed trial randomizing patients with cancer of unknown primaryu (CUP) to treatment based on expression profiling results or to usual care. The evidence is insufficient to determine the effects of the technology on net health outcomes.
In July 2008, the PathWork® Tissue of Origin Test™ (Response Genetics; now Cancer Genetics) was cleared for marketing with limitations (see below) by the U.S. Food and Drug Administration (FDA) through the 510(k) process. 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, metastatic cases) that were diagnosed according to current clinical and histopathologic practice. The database contains examples of RNA expression patterns for 15 common malignant tumor types.
A PathWork® Tissue of Origin® Test result was 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:
In June 2010, the PathWork® Tissue of Origin Test Kit-FFPE was cleared for marketing by FDA through the 510(k) process. The 2010 clearance was an expanded application, which permitted 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 FDA through the 510(k) process.
The test is now offered by Cancer Genetics, as the Tissue of Origin® test.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). CancerTYPE ID® (Biotheranostics, San Diego, CA) or RosettaGX Cancer Origin™ (Rosetta Genomics, Philadelphia, PA) are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Current National Comprehensive Cancer Network (NCCN) guidelines for occult primary version 1.2018 address molecular profiling to identify the tissue of origin in cancer unknown primary (CUP). The guideline states:
Over the past decade, studies have examined various molecular assays designed to identify the tissue of origin in CUP (cancer unknown primary). These assays are designed based on the assumption that metastatic tumors will have similar molecular profiles to that of the primary tumor of origin. Assays used in GEP utilize messenger RNA (mRNA) DNA, or microRNA (miRNA) based platforms. When validated using samples from known tumor types, these assays have generally demonstrated an accuracy rate of 85% to 90%. Because it is difficult to confirm the site of origin in most cases of CUP, the accuracy of GEP assays in occult primary tumor samples is challenging to determine. Surrogate measures used to determine accuracy include correlation with IHC findings, clinical presentation/response to therapy, as well as appearance of latent disease at the primary tumor site. Several studies suggest that GEP profiling is comparable or superior to the accuracy of IHC for poorly differentiated/undifferentiated carcinomas.
In addition to DNA and mRNA based assays, miRNA based assays have also generated interest for their potential to identify tissue of origin. These assays examine the presence of specific miRNAs, which are noncoding RNAs that regulate gene expression and show high tissue specificity.
Several commercially available GEP tests have been evaluated in prospective clinical studies in an attempt to determine if the information they provide translates into clinically meaningful benefits for patients.
Recent reviews have compared the commercially available GEP tests. As noted, outcomes data are not currently available to recommend routine use of molecular profiling in the workup of CUP (cancer unknown primary). Likewise, no such data exist to endorse the automatic or indiscriminate use of IHC. Until more robust outcomes and comparative effectiveness data are available, pathologist and oncologists must collaborate on the judicious use of these modalities on a case by case basis, with the best possible individualized outcome in mind.
A 2010 clinical guidance from the National Institute for Health and Care Excellence recommended against the use of gene expression profiling (GEP) to identify primary tumors in patients with cancers of unknown primary (CUPs) or when deciding which treatment to offer patients with confirmed CUP. This recommendation was based on “limited evidence that gene-expression based profiling changes the management of patients with CUP and no evidence of improvement in outcome.” The guidance included a research recommendation for trials to assess the clinical utility of GEP.
The 2015 guideline from the European Society of Medical Oncology (ESMO) cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up states that “several gene expression profiling assays have become commercially available claiming to blindly and correctly identify a known primary cancer and a likely tissue of origin in patients with cancer of unknown primary (CUP). These assays are based on mRNA, miRNA RT-PCR or oligonucleotide microarray technologies. No significant differences in the tumor microRNA expression profile were evident when cancer of unknown primary (CUP) metastases biologically assigned to a primary tissue origin were compared with metastases from typical solid tumors of known origin. These tests may aid in the diagnosis of the putative primary tumor site in some patients, however, their impact on patient outcome via administration of primary site specific therapy remains questionable and unproven in randomized trials”. (IV, C)
IV Retrospective cohort studies or case-control studies; C insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, cost, etc.) Optional
Gene expression profiling including but not limited to the following is considered investigational to evaluate the site of origin of a tumor of unknown primary, or to distinguish a primary from metastatic tumor:
To date, based on review of the peer reviewed medical literature the majority of the available studies fail to provide sufficient evidence that gene expression profiling to identify the tissue of origin for cancers of unknown primary lead to improved health outcomes (i.e., clinical utility). Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling to identify the tissue of origin for cancers of unknown primary site compared with traditional clinicopathologic factors to guide medical management and improve clinical outcomes.
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