Medical Policy

 

Subject: Molecular Profiling and Proteogenomic Testing for the Evaluation of Malignant Tumors
Document #: GENE.00025 Publish Date:    08/29/2018
Status: Revised Last Review Date:    07/26/2018

Description/Scope

This document addresses multi-biomarker molecular profiling and proteogenomic testing for the evaluation of malignant tumors in persons who have been diagnosed with cancer. Commercially available molecular profile panels include, but may not be limited to:

Proteogenomic tests include, but may not be limited to:

When an individual genetic test included in a profile is separately addressed in a separate medical policy, that policy document applies.

Note: This document does not address circulating tumor DNA (ctDNA) or circulating tumor cell (CTC) tests. For information on these tests, please see the following:

Note: For additional information please see the following related documents:

Position Statement

Medically Necessary:

Molecular profiling is considered medically necessary when all of the criteria below are met:

  1. Individual has been diagnosed with stage IV or recurrent non-small cell lung cancer (NSCLC); and
  2. The test is used to assess tumor mutation burden and identify candidates for checkpoint inhibition immunotherapy; and
  3. The test is performed using a formalin-fixed paraffin-embedded tumor tissue sample.

Investigational and Not Medically Necessary:

Molecular profiling is considered investigational and not medically necessary for all other indications.

Proteogenomic testing is considered investigational and not medically necessary for all indications.

Rationale

Molecular Profiling

Molecular profiling, also called comprehensive genomic profiling, is a method for identifying multiple biomarkers in the malignant tumors of persons who have cancer. The biomarker information can be used to identify treatment options. The personalized tumor molecular profiling services or test panels addressed in this document are similar in that they all evaluate tumor tissue and, from it, produce a molecular profile of the tumor and a list of potential therapies. However, their individual testing methods vary from matching over expressed genes with drugs to more complex systems biology approaches.

FoundationOne

FoundationOne uses next generation sequencing (NGS) “to interrogate the entire coding sequence of 236 cancer-related genes (3769 exons) plus 47 introns from 19 genes frequently altered or rearranged in cancer.” FoundationOne helps match the genomic alterations present in a tumor with specific targeted therapies or clinical trials. Recent small studies (Drilon, 2013; Lipson, 2012; Vignot, 2013) have investigated next generation sequencing in individuals with lung cancer. Others have used next generation sequencing in those with breast cancer (Ross, 2013a); colorectal and other gastrointestinal cancers (Dhir, 2017; Gong, 2017; Lipson, 2012), ovarian cancer (Ross, 2013b), and prostate cancer (Beltran, 2013). Limitations of these studies include small sample sizes and lack of randomization. At this time, the FoundationOne test has not been approved by the U.S. Food and Drug Administration (FDA).

FoundationOne CDx

On November 30, 2017, the FDA approved the FoundationOne CDx NGS sequencing test as a companion diagnostic for several drugs including: Gilotrif® (afatinib), Iressa® (gefitinib), Tarceva® (erlotinib), Tagrisso® (osimertinib), Alecensa® (alectinib), Xalkori® (crizotinib), Zykadia® (ceritinib), Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib), Tafinlar® (dabrafenib), Zelboraf® (vemurafenib), Mekinist® (trametinib), Cotellic® (cobimetinib) in combination with Zelboraf® (vemurafenib), Herceptin® (trastuzumab), Kadcyla® (ado-trastuzumabemtansine), Perjeta® (pertuzumab), Erbitux® (cetuximab), Vectibix® (panitumumab), and Rubraca® (rucaparib). In addition, the test detects substitutions and alterations in 324 genes and is indicated to provide general tumor mutation profiling of solid malignant neoplasms in accordance with professional guidelines in oncology. The FDA Summary of Safety and Effectiveness notes that FoundationOne CDx is a new test that has never been marketed in the United States.

The FDA approval was based on concordance studies that compared the Foundation One CDx test to approved specific companion diagnostic tests including the cobas® EGFR Mutation Test (EGFR exon 19 deletions, L858R, EGFR T790M), Ventana ALK CDx Assay (ALK), Vysis ALK Break-Apart FISH Probe Kit (ALK), therascreen® KRAS RGQ PCR Kit (KRAS), Dako HER2 FISH pharmDx® Kit (ERBB2 [HER2]), cobas® BRAF V600 Mutation Test (BRAF V600), THxID BRAF kit (BRAF V600), and FoundationFocus CDxBRCA (BRCA1 and BRCA2). The sample size for each biomarker comparison study ranged from 175 to 342, the positive percent agreement ranged from 89.4% to 100%, and the negative percent agreement ranged from 86.1% to 100%. For the BRCA1 and BRCA2 mutation, the FoundationOne CDx was considered concordant based on the previous approval of the FoundationFocus CDxBRCA test. The FDA states, “The clinical concordance studies, with the exception of ALK and EGFR T790M, were subject to pre-screening bias, therefore the concordance results may be overestimated and the failure rate may be underestimated.” For the T790M mutation, there is ongoing research to determine why a subset population with a mutant allele frequency < 5% tested negative with the cobas EGFR Mutation Test v2 but tested positive with the FoundationOne CDx test. The FDA concluded that, overall, the FoundationOne CDx test demonstrated non-inferiority to the corresponding specific companion diagnostic tests (FDA, 2017a). On March 16, 2018, the Centers for Medicare and Medicaid Services (CMS) approved NGS-based in vitro companion diagnostic laboratory tests for national coverage after an FDA-CMS parallel review.

In 2018, Hellmann and colleagues reported results from the CheckMate 227 study, an open-label, phase 3 trial (NCT02477826) designed to evaluate the efficacy of nivolumab or nivolumab-based regimens as first-line therapy in participants with stage IV or recurrent NSCLC that have not previously received chemotherapy as primary therapy. Trial participants were stratified into PD-L1 expression levels (at least 1% or less than 1%). In addition, tumor mutation burden was determined using the FoundationOne CDx assay. At 1 year, the progression-free survival (PFS) rate for participants with a high tumor mutation burden that received nivolumab in combination with ipilimumab was 42.6% versus 13.2% for the chemotherapy group. The median PFS was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) for participants that received nivolumab in combination with ipilimumab versus 5.5 months for the chemotherapy group (95% CI, 4.4 to 5.8) (HR for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The authors concluded:

Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection.

Molecular Intelligence Service or Target Now

A widely used tumor molecular profile has been the Target Now Molecular Profiling Service. According to the Caris Life Sciences website, their tumor profiling service is now being promoted as the Molecular IntelligenceService. The published literature addressing these services is limited. Von Hoff and colleagues (2010) evaluated 86 individuals with refractory metastatic cancer. PFS using a treatment regimen selected by Target Now molecular profiling of a malignant tumor was compared with the PFS of the most recent treatment regimen on which the individual experienced progression. A molecular target was detected in 84 of 86 (98%) participants. A total of 66 (78.6%) individuals were treated according to the molecular profile results with 18 of the 66 (27%) having a PFS ratio (defined as PFS on molecular profile–selected therapy or PFS on prior therapy) of greater than or equal to 1.3 (95% CI, 17% to 38%; p=0.007).

An editorial (Doroshow, 2010) accompanying the study reported that the trial had a number of significant limitations, including uncertainty surrounding the achievement of time to progression (the study’s primary endpoint), and a lack of a randomized design. Additional limitations include a small number of participants and lack of duplication of study results by an independent dataset.

Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)

Cheng and colleagues (2015) developed and evaluated the MSK-IMPACT, “a hybridization capture-based assay targeting all coding regions of 341 oncogenes and tumor suppressors.” The ability of the assay to detect single nucleotide variants (SNVs) and short insertions and deletions (indels) was assessed in 284 known positive solid tumor samples. Of these, 75 had a matched normal sample available. The authors reported successful detection of known variants in all 284 cases, and ability to achieve high degrees of resolution and levels of coverage to > 500x in tumor samples that allows low-frequency mutations to be detected. On November 15, 2017, the FDA granted marketing authorization for MSK-IMPACT based on a de novo request (FDA 2017b).

Other Molecular Profiling

Other molecular profiling such as EXaCT-1 Whole Exome Sequencing, GeneKey, GeneTrails Solid Tumor Panel, MatePair, MyAML, OmniSeq, OnkoMatch, OncInsights, and SmartGenomics have less published validation. To date, there is insufficient peer-reviewed evidence specifically validating these tests.

In 2012, Tsimberidou and colleagues developed a personalized medicine program at a single facility in the context of early clinical trials. Their goal was to observe whether molecular analysis of advanced cancer and use of targeted therapy to counteract the effects of specific aberrations would be associated with improved clinical outcomes. Participants with advanced or metastatic cancer refractory to standard therapy underwent molecular profiling. A total of 175 subjects were treated with matched therapy, and the overall response rate was 27%. Of the 116 subjects treated with non-matched therapy, the response rate was 5%. The median time-to-failure was 5.2 months for those on matched therapy versus 2.2 months on non-matched therapy. At a median of 15 months follow-up, median survival was 13.4 months versus 9.0 months in favor of matched therapy.

Jameson and colleagues (2013) performed a small pilot study investigating multi-omic molecular profiling (MMP) for the selection of breast cancer treatment. MMP treatment recommendations were selected in 25 cases and original treatment plans were revised accordingly. Partial responses were reported in 5/25 (25%), stable disease in 8/25 (32%) and 9/25 had no disease progression at 4 months. This study was limited by its small size and non-randomization. A large randomized prospective trial is needed for further evaluation.

Primarily marketed to researchers, Life Technologies Inc. offers several variations of their Ion Torrent™ Next Generation Sequencing Ion AmpliSeq™ panels, according to the company website. The Ion AmpliSeq Comprehensive Cancer Panel analyzes more than 400 cancer-related genes and tumor suppressor genes. The Ion AmpliSeq Cancer Hotspot Panel v2 analyzes the “hotspot” regions of 50 cancer-related and tumor suppressor genes.

Studies on Molecular Profiling Therapy

LeTourneau and colleagues (2012, 2015) reported on an open-label, randomized controlled phase II trial of treatment of refractory metastatic solid tumors directed by molecular profiling versus standard of care treatment (SHIVA trial). A total of 195 adults, consisting of 99 in the experimental group and 96 in the control group, were enrolled from eight academic centers in France. The primary outcome was progression-free survival (PFS) analyzed by intention-to-treat. Randomization was stratified by three molecular pathways (hormone receptor pathway, PI3K/AKT/mTOR pathway, and RAF/MEK pathway). Molecular analysis included targeted next generation sequencing (NGS), gene copy number alterations and hormone expression by immunohistochemistry. The molecularly targeted drugs used in the experimental group were approved for clinical use in France, but were outside their indications. The control group received standard treatment chosen by the physician. Median follow-up was 11.3 months for both the experimental and control groups at the time of primary analysis of PFS. Median PFS was 2.3 months (95% CI, 1.7-3.8) in the experimental group versus 2.0 months (95% CI, 1.7-2.7 months) in the control group (hazard ratio, 0.88; 95% CI, 0.65-1.19; p=0.41). Upon subgroup analysis, there was no statistically significant difference in PFS between the two groups. Objective responses were reported for 4 of 98 (4.1%) assessable subjects in the targeted treatment group versus 3 of 89 (3.4%) assessable subjects in the standard care group. Among the safety population, grade 3-4 adverse events were reported for 43 of the 100 subjects (43%) who received a molecularly targeted agent and 32 (35%) of 91 subjects treated in the control group. The authors suggested that “off-label use of molecularly targeted agents should be discouraged and enrollment in clinical trials should be encouraged to help identify predictive biomarkers of efficacy.”

Presley and colleagues (2018) conducted a multicenter, retrospective, cohort study to compare broad-based genomic sequencing to routine EGFR and ALK biomarker testing in individuals with advanced NSCLC (stage IIIB/IV or unresectable nonsquamous). The primary outcomes were the 12-month mortality and overall survival from the start of first-line treatment. The researchers examined the Flatiron Health Database records of 5688 individuals (median age 67 years) who received care for advanced NSCLC between January 1, 2011 and July 31, 2016: 875 received broad-based genomic sequencing (multigene panel testing assay of more than 30 genes) and 4813 received routine EGFR/ALK testing. Subjects were required to have documented broad-based genomic sequencing testing or EGFR testing; if EGFR was negative, ALK testing was required. All subjects received at least one line of systemic antineoplastic treatment. At 12 months, the unadjusted mortality rates were 49.2% for the broad-based group and 35.9% for the EGFR/ALK group. Of the subjects in the broad-based group, 4.5% received targeted treatment based on test results, 9.8% received EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. When using an instrumental variable analysis, no significant association was found between broad-based genomic sequencing and 12-month mortality (difference in the predicted probability of death at 12 months between the groups: −3.6%; 95% CI, −18.4% to 11.1%; p=0.63). The predicted probability of 12-month mortality was 44.4% (95% CI, 42.9% to 45.9%) in the EGFR/ALK group and 41.1% (95% CI, 27.7% to 54.5%) in the broad-based group. For the propensity score-matched sample, the overall survival was not significantly different between the groups (42.0% vs. 45.1%; 0.92 HR; 95% CI, 0.73 to 1.11; p=0.40). The researchers concluded that “among patients receiving care for advanced NSCLC in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.” Limitations of the study included a relatively small and homogenous sample for the broad-based group and the possible inaccuracy of the electronic health records.

Other Considerations

The NCCN guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of biomarkers. However, the guidelines do contain recommendations for specific genetic testing for individual cancers, when there is a known drug-biomarker combination that has demonstrated benefits for that particular type of tumor, such as colon or non-small cell lung cancer (NSCLC). In order to conserve tissue, the current NSCLC guidelines support an FDA approved NGS companion diagnostic test that can simultaneously test for EGFR mutations, BRAF mutations, ROS1 rearrangements, and ALK rearrangements.

A 2018 joint guideline (Lindeman, 2018), Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors, from the CAP, International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) states that “multiplexed genetic sequencing panels are preferred over multiple single-gene tests to identify other treatment options beyond EGFR, ALK, and ROS1” (level of evidence rating: expert consensus opinion - serious limitations in quality of evidence). However, the authors note that “the strength of evidence is inadequate supporting the use of multiplexed genetic sequencing panels compared with single-gene tests.”

Conclusion

In summary, there is insufficient published evidence to support the wide use of molecular profiling to guide treatment decisions for malignant tumors. The available published literature consists of one randomized controlled trial, a small number of uncontrolled studies, and non-randomized trials that use imperfect comparators.

Proteogenomics

Proteogenomics refers to the complex integration of genomic, proteomic, and transcriptomic data to provide a more comprehensive picture of the function of the genome. Proteogenomic testing differs from proteomic testing in that proteomic testing is typically limited to the measurement of protein products alone without the inclusion of genomic and transcriptomic information.

Research on the use of proteogenomic testing for individuals with oncologic conditions is in the early stages of development and has primarily focused on the diagnostic, prognostic, and predictive value of proteogenomics in various cancers. Examples of proteogenomic tests in the United States include the GPS Cancer test and the DarwinOncoTarget test. At the time of this review, no peer-reviewed published evidence on the clinical validity or utility of these tests and no guidelines or recommendations by professional medical societies or governmental organizations were identified.

Several studies have been published in the past few years on whole exome and tumor-normal sequencing, which may be applicable to one component of the GPS cancer test (Beltran, 2015; Jones, 2015; Mandelker, 2017; Teer, 2017).  These studies have described the ability of whole exome and tumor-normal sequencing to identify individuals within a population with inheritable genetic mutations with potential clinical ramifications, including the identification of mutations for which specific pharmacological therapies are available, in a rare percentage of the time. However, the methods used are not the same as the GPS test and these studies do not provide any data related to clinical or health-related outcomes that may result from the use of whole exome and tumor-normal sequencing, let alone the GPS test. These remain outstanding questions that need to be addressed in properly designed and conducted trials.

Conclusion

There is insufficient information to draw conclusions regarding the clinical validity or utility of commercial proteogenomic tests in the diagnosis, prognosis, or management of individuals with oncologic conditions. Additional research is needed to determine if these tests result in improved health outcomes and which population of individuals with oncologic conditions might benefit.

Background/Overview

Cancer is a significant health problem in the United States. The American Cancer Society estimates there will be 1,735,350 new cancer diagnoses and 609,640 cancer-related deaths in 2018. In general, tumor location, stage, grade, and the individual’s underlying physical condition have been used in the clinical setting to determine the specific therapeutic approach to a certain cancer.

Molecular Profiling

The use of individual molecular markers in cancer management is well established; however, the use of comprehensive molecular profiling to evaluate malignant tumors is evolving. The rationale for molecular profiling is that more complete knowledge of molecular marker status may alter treatment and possibly improve individual outcomes. Examples of commercially available multiple molecular testing panels are described below.

EXaCT-1 Whole Exome Sequencing explores 22,000 genes in healthy and malignant cells and helps pathologists find alterations in the cancer-development process. As a whole-exome sequencing test, it may be effective for the treatment of advanced-stage cancer when other treatments have failed. The test requires a tumor tissue sample and matched normal sample (the normal sample can be from whole blood or a cheek swab).

FoundationOne is a genomic profile intended to supplement traditional cancer treatment decision tools by matching each person tested with targeted therapies relevant to the molecular changes in their tumor. The company, Foundation Medicine retrieves the tumor sample from the pathology laboratory, sequences and analyzes the tumor and sends an interpretive report for each person tested. The report highlights molecular changes that may potentially guide therapy and provide scientific and medical literature to evaluate potential treatment options.

FoundationOne CDx is an NGS genomic profile test, similar to Foundation One, which is able to identify substitutions, insertion and deletion alterations, and copy number alterations in 324 genes, gene rearrangements, and genomic signatures. In addition, the test is an in vitro companion diagnostic for several cancer medications.

Molecular Intelligence Service or Target Now Molecular Profiling Service begins with an immunohistochemistry analysis and if there is a frozen sample of tumor tissue available, a gene expression analysis by microarray may be performed. Additional tests may be added including: fluorescent in-situ hybridization to examine gene copy number variation in the tumor; polymerase chain reaction or deoxyribonucleic acid (DNA) sequencing to determine gene mutations in the DNA tumor. The results from each test are then applied to the published findings from cancer researchers and potential treatment options are subsequently generated. The Molecular Intelligence Service is promoted in a similar manner and is said to be available in several levels of service, “allowing the physician to customize the level of profiling they deem necessary for each patient.”

GeneKey profiles a tumor genome through whole genome mRNA expression profiling and copy number variant detection. A fresh biopsy specimen is initially obtained and sent to a laboratory that runs GeneKey-specified tests. Analysis is performed by proprietary systems biology approaches. A scientific team from GeneKey is sent to present results of potential treatment options, scientific rationale and relevant literature citations to the treating physician and the individual being tested.

OncInsights also begins with a fresh tumor sample obtained by biopsy. The lab processes the sample measuring genes and molecular data points to create a molecular pathway map of the individual’s disease. The data is then processed by the company’s bioinformatics platform, which analyzes information using a series of algorithms to identify key drug targets or signatures of drug response/resistance. The individual’s unique profile is then compared to molecularly targeted drug databases to align disease characteristics with potential treatment options. Related scientific and clinical evidence are then located and a personalized report is generated.

The GeneTrails Solid Tumor Panel provides information for 37 genes known to have mutations in solid tumors. For 20 of the 37 genes, the presence of a mutation might justify the use of an FDA-approved therapeutic and 17 have mutations that might support clinical trial eligibility.

OnkoMatch is a polymerase chain reaction (PCR)-based gene panel that detects 68 mutations (single nucleotide polymorphisms) in 14 oncogenes and tumor suppressor genes that are associated with solid tumors.

The Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) is a hybridization capture-based NGS assay that detects mutations, variants, and structural rearrangements. The MSK-IMPACT test offers paired analysis of solid tumor tissue with matched normal tissue to determine somatic cancer mutations to guide treatment decisions.

SmartGenomics is a cancer specific test consisting of multiple diagnostic panels targeting a variety of cancers including lung, colon, brain and thyroid cancer. The service provider, PathGroup indicates that results will assist physicians “to make more precise therapeutic recommendations and clinical management decisions.”

MyAML is an NGS panel that analyzes the coding and non-coding exons of 200 genes (194 AML [acute myeloid leukemia] specific genes), including the breakpoint hotspots within 36 genes.

The MatePair acute myeloid leukemia NGS panel assists with the classification and prognosis of AML using 19 genes.

OmniSeq Advance is an NGS test that aids in the therapeutic management of advanced cancer by performing RNA sequencing of over 50 immune markers and profiling 144 genes.

Proteogenomics

Whereas genomic study examines all of the genes of an organism, proteomic study addresses all of the proteins expressed by those genes. Proteogenomics combines proteomic and genomic data. In this approach, customized protein sequence databases employ genomic and transcriptomic information to help identify novel peptides not found in reference protein sequence databases. The proteomic data provides protein-level evidence of gene expression and helps to refine gene models. Due in large part to the emergence of next generation sequencing technologies such as RNA sequencing and improvements in the depths and throughput of mass spectrometry-based proteomics, the pace of proteogenomics research has greatly accelerated (Nesvizhskii, 2014).

Proteogenomics may someday provide a detailed analysis of the molecular components and underlying mechanisms associated with the development of various cancers. This work is driven in part by the hypothesis that a better understanding of both proteomics and genomics will improve diagnosis and treatment decisions in individuals with oncologic conditions. Potential clinical applications of proteogenomics include, but are not limited to:

According to information on the NantHealth website, the GPS Cancer test integrates quantitative targeted proteomics detected by mass spectrometry with whole transcriptome and whole genome sequencing, of both cancer tissue and normal tissue. The GPS Cancer test is marketed as a tool to diagnose molecular alterations in an individual’s cancer, and to identify personalized therapeutic regimens.

DarwinOncoTarget is described as a diagnostic platform that “detects and assesses the full repertoire of aberrantly active and pharmacologically actionable proteins” in a tumor sample that is independent of the DNA mutational state. A report is generated that identifies the proteins and target drugs/investigational compounds that may be used.

The White House Office of the Vice President of the United States has announced an international collaboration between the National Cancer Institute (NCI) at the National Institutes of Health in the United States, and Macquarie University, Children's Medical Research Institute, Garvan Institute of Medical Research, and Bioplatforms Australia Limited in Australia, to facilitate scientific collaborations in the field of clinical proteogenomic studies and their translation to cancer care. Additionally, the State governments of New South Wales and Victoria have signed separate agreements with the NCI that will construct a general framework of collaboration for promoting and conducting high-quality research and data-sharing to strengthen the evidence base necessary for cancer prevention, treatment, and management. As part of the Cancer Moonshot, it is hoped that this international partnership will break down silos and allow scientists to work together and share information, with the goal of ending cancer as we know it (NCI, 2016).

As a result of the interest in proteogenomic research, several databases are under construction. These databases include but are not limited to the Human Protein Reference Database, Human Cancer Proteome Variation Database and the Cancer Mutant Proteome Database.

Definitions

Cancer Moonshot: A collaborative effort between the public and private sectors (including but not limited to the governments, researchers, healthcare providers, data and technology experts, patients, families, and patient advocates) to make a decade’s worth of advances in the understanding, prevention, diagnosis, treatment, and care of cancer in 5 years beginning in 2016.

Checkpoint Inhibition Immunotherapy (or Checkpoint Inhibitors):  A type of drug (monoclonal antibody) that blocks certain proteins produced by immune T cells and cancer cells that keep the immune system in check and prevent the T cells from attacking cancer cells.  By blocking these proteins, checkpoint inhibitors thus unleash the immune T cells to kill the cancer cells.  The following is a list of FDA-approved checkpoint inhibitor drugs.

Copy number variant: An alteration of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA.

Genome: The total genetic composition of an organism.

Genomic data: Information derived from the sequencing of DNA or RNA fragments.

Immunohistochemistry: The process of detecting proteins in the cells of a tissue section.

Indel: A genomic insertion or deletion.

Messenger ribonucleic acid (mRNA): A molecule that results when a cell "reads" a DNA strand.

Molecular profiling services: Laboratory services which catalogue a number of genetic markers in an attempt to select optimal therapy.

Next-generation sequencing: Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.

Proteome: The complete set of proteins expressed by a genome.

Proteomic data: Data related to the functioning of protein; generally obtained using a combination of liquid chromatography and tandem mass spectrometry.

Proteomics: The comprehensive and integrative study of proteins and their biological functions.

Transcriptome: The sum total of all the messenger RNA molecules expressed from the genes in a specified cell population or organism. May also be defined as the array of mRNA transcripts expressed in a particular cell or tissue type.

Tumor Mutation Burden: A biomarker used to assess responsiveness to immunotherapy by measuring the total number of mutations per coding area of a tumor genome. Tumor Mutation Burden is typically determined by molecular (genomic) profiling with a large multigene assay/panel.

Whole genome (DNA) sequencing: A laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a single time. Also known as full genome sequencing (FGS), complete genome sequencing, or entire genome sequencing.

Whole transcriptome (RNA) sequencing: A next-generation sequencing technique used to identify and measure RNA in a biological sample at a given moment in time. Also known as RNA sequencing and whole transcriptome shotgun sequencing.

Coding

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

When services may be Medically Necessary when criteria are met:

CPT

 

81445

Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

81455

Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

81479

Unlisted molecular pathology procedure [when specified as molecular profiling for NSCLC]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as molecular profiling for NSCLC]

88363

Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis) [when in conjunction with molecular profiling for NSCLC]

0037U

Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
FoundationOne CDx™ (F1CDx); Foundation Medicine, Inc.

0048U

Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)
MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets); Memorial Sloan Kettering Cancer Center

 

 

ICD-10 Diagnosis

 

C34.00-C34.92

Malignant neoplasm of bronchus and lung

C78.00-C78.02

Secondary malignant neoplasm of lung

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81425

Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis

81450

Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed

81479

Unlisted molecular pathology procedure [when specified as molecular profiling for malignant tumors (other than NSCLC) or proteogenomic testing, such as the GPS Cancer test or DarwinOncoTarget]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as molecular profiling for malignant tumors other than NSCLC]

88363

Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis) [when in conjunction with molecular profiling for malignant tumors other than NSCLC]

0013U

Oncology (solid organ neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, fresh or frozen tissue or cells, report of specific gene rearrangement(s)
MatePair Targeted Rearrangements, Oncology, Mayo Clinic

0014U

Hematology (hematolymphoid neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood or bone marrow, report of specific gene rearrangement(s)
MatePair Targeted Rearrangements, Hematologic, Mayo Clinic

0036U

Exome (ie, somatic mutations), paired formalin-fixed paraffin-embedded tumor tissue and normal specimen, sequence analyses
EXaCT-1 Whole Exome Testing; Lab of Oncology-Molecular Detection, Weill Cornell Medicine Clinical Genomics Laboratory

0050U

Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements
MyAML NGS Panel; LabPMM LLC, an Invivoscribe Technologies, Inc. Company

0056U

Hematology (acute myelogenous leukemia), DNA, whole genome next generation sequencing to detect gene rearrangement(s), blood or bone marrow, report of specific gene rearrangement(s)
MatePair Acute Myeloid Leukemia Panel; Mayo Clinic

0057U

Oncology (solid organ neoplasia), mRNA, gene expression profiling by massively parallel sequencing for analysis of 51 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a normalized percentile rank
RNA-Sequencing by NGS; OmniSeq, Inc., Life Technologies Corporation

 

 

ICD-10 Diagnosis

 

C00.0-C80.2

Malignant neoplasms

C81.00-C86.6

Hodgkin and non-Hodgkin lymphomas

References

Peer Reviewed Publications:

  1. Ansong C, Purvine SO, Adkins JN, et al. Proteogenomics: needs and roles to be filled by proteomics in genome annotation. Brief Funct Genomic Proteomic. 2008; 7(1):50-62.
  2. Armengaud J. A perfect genome annotation is within reach with the proteomics and genomics alliance. Curr Opin Microbiol. 2009; 12(3):292-300.
  3. Beltran H, Eng K, Mosquera JM, et al. Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response. JAMA Oncol. 2015; 1(4):466-474.
  4. Beltran H, Yelensky R, Frampton GM. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013; 63(5):920-926.
  5. Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015; 17(3):251-264.
  6. Dhir M, Choudry HA, Holtzman MP, et al. Impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies. Cancer Med. 2017; 6(1):195-206.
  7. Doroshow JH. Selecting systemic cancer therapy one patient at a time: is there a role for molecular profiling of individual patients with advanced solid tumors? J Clin Oncol. 2010; 28(33):4869-4871.
  8. Drilon A, Wang L, Hasanovic A. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013; 3(6):630-635.
  9. Garber K. Ready or not: personal tumor profiling tests take off. J Natl Cancer Inst. 2011; 103(2):84-86.
  10. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883-892.
  11. Gong J, Cho M, Sy M, et al. Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience. Oncotarget. 2017; 8(26):42198-42213.
  12. Hellmann MD, Ciuleanu TE, Pluzanski A, et al.  Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018; 378(22):2093-2104.
  13. Huang PJ, Lee CC, Tan BC, et al. CMPD: cancer mutant proteome database. Nucleic Acids Res. 2015; 43(Database issue):D849-855.
  14. Jameson GS, Petricoin EF, Sachdev J, et al. A pilot study utilizing multi-omic molecular profiling to find potential targets and select individualized treatments for patients with previously treated metastatic breast cancer. Breast Cancer Res Treat. 2014; 147(3):579-588.
  15. Jones S, Anagnostou V, Lytle K, et al. Personalized genomic analyses for cancer mutation discovery and interpretation. Sci Transl Med. 2015; 7(283):283ra53.
  16. Keshava Prasad TS, Goel R, Kandasamy K, et al. Human Protein Reference Database--2009 update. Nucleic Acids Res. 2009; 37(Database issue):D767-772.
  17. Le Tourneau C, Delord JP, Gonçalves A, et al.; SHIVA Investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015; 16(13):1324-1334.
  18. Le Tourneau C, Kamal M, Trédan O, et al. Designs and challenges for personalized medicine studies in oncology: focus on the SHIVA trial. Target Oncol. 2012; 7(4):253-265.
  19. Lipson D, Capelletti M, Yelensky R. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012; 18(3):382-384.
  20. Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing.  JAMA. 2017; 318(9):825-835.
  21. Mukherjee S, Ma Z, Wheeler S, et al. Chromosomal microarray provides enhanced targetable gene aberration detection when paired with next generation sequencing panel in profiling lung and colorectal tumors. Cancer Genet. 2016; 209(4):119-129.
  22. Nesvizhskii AI. Proteogenomics: concepts, applications and computational strategies. Nat Methods. 2014; 11(11):1114-1125.
  23. Presley CJ, Tang D, Soulos PR, et al. Association of broad-based genomic sequencing with survival among patients with advanced non–small cell lung cancer in the community oncology setting. JAMA. 2018; 320(5):469–477.
  24. Renuse S, Chaerkady R, Pandey A. Proteogenomics. Proteomics. 2011; 11(4):620-630.
  25. Rivers RC, Kinsinger C, Boja ES, et al. Linking cancer genome to proteome: NCI's investment into proteogenomics. Proteomics. 2014; 14(23-24):2633-2636.
  26. Ross JS, Ali SM, Wang K. Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies. Gynecol Oncol. 2013a; 130(3):554-559.
  27. Ross JS, Wang K, Sheehan CE. Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. Clin Cancer Res. 2013b; 19(10):2668-2676.
  28. Subbannayya Y, Pinto SM, Gowda H, et al. Proteogenomics for understanding oncology: recent advances and future prospects. Expert Rev Proteomics. 2016; 13(3):297-308.
  29. Teer JK, Zhang Y, Chen L, et al. Evaluating somatic tumor mutation detection without matched normal samples. Hum Genomics. 2017; 11(1):22.
  30. Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res. 2012; 18(22):6373-6383.
  31. Vignot S, Frampton GM, Soria JC. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. 2013; 31(17):2167-2172.
  32. Von Hoff DD, Stephenson JJ Jr., Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010; 28(33):4877-4883.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Centers for Medicare and Medicaid Services (CMS). Decision memo for next-generation sequencing (NGS) for Medicare beneficiaries with advanced cancer. CAG-00450N. March 16, 2018. Available at: https://www.cms.gov/medicare-coverage-database/‌‌details/nca-decision-memo.aspx?NCAId=290&SearchType‌=Advanced&CoverageSelection. Accessed on June 25, 2018.
  2. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018; 142(3):321-346.
  3. NCCN Clinical Practice Guidelines in Oncology™. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on June 25, 2018.
    • Colon cancer (V2.2018). March 14, 2018.
    • Non-small cell lung cancer (V4.2018). April 26, 2018.
  4. U.S. Food and Drug Administration Premarket Approval Database. FoundationOne CDx Summary of Safety and Effectiveness. No. P170019. Rockville, MD: FDA. November 30, 2017a. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019B.pdf. Accessed on June 25, 2018.
  5. U.S. Food and Drug Administration De Novo Database. MSK-IMPACT Decision Summary. DEN170058. Rockville, MD: FDA. November 15, 2017b. Available at: https://www.accessdata.fda.gov/cdrh_docs/‌reviews/‌‌DEN170058.pdf. Accessed on June 25, 2018.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org. Accessed on June 25, 2018.
  2. Office of Cancer Clinical Proteomics Research, National Cancer Institute. Proteomics and Proteogenomics. https://proteomics.cancer.gov/. Accessed on June 25, 2018.
Index

Caris Life Sciences Molecular Intelligence Service
Caris Target Now
Caris Test
DarwinOncoTarget
EXaCT-1 Whole Exome Sequencing
FoundationOne
FoundationOne CDx
GeneKey
GPS Cancer Test
Ion Torrent Next Generation Sequencing Ion AmpliSeq
MatePair
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
Multi-Omic Molecular Profiling (MMP)
MyAML
OmniSeq Advance
OncInsights
Proteogenomic Test
SmartGenomics
Target Now Molecular Profiling Service

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

Document History

Status

Date

Action

Revised

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

07/25/2018

Hematology/Oncology Subcommittee review. Added MN statement for molecular profiling. The Description/Scope, Rationale, Background, Coding, References, Websites, and Index sections updated.

Reviewed

05/03/2018

MPTAC review.

Reviewed

05/02/2018

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Description/Scope, Rationale, Background, References, and Websites sections. Updated Coding section with 07/01/2018 CPT changes; added 0048U, 0050U, 0056U, 0057U.

 

03/29/2018

Updated Coding section with 04/01/2018 CPT changes; added PLA codes 0036U, 0037U.

Reviewed

11/02/2017

MPTAC review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale and References sections.

 

08/01/2017

Updated Coding section with 08/01/2017 CPT PLA code changes

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Investigational and NMN statement added for proteogenomic testing. Description, Rationale, Background, Definitions, Coding, References and Index sections updated.

Reviewed

11/05/2015

MPTAC review.

Reviewed

11/04/2015

Hematology/Oncology Subcommittee review. Description, Background and Reference sections updated. Updated Coding section with 01/01/2016 CPT descriptor changes, and also removed ICD-9 codes.

Reviewed

11/13/2014

MPTAC review.

Reviewed

11/12/2014

Hematology/Oncology Subcommittee review. Rationale, Background, Reference and Index sections updated. Updated Coding section with 01/01/2015 CPT changes.

Revised

11/14/2013

MPTAC review.

Revised

11/13/2013

Hematology/Oncology Subcommittee review. Brand names removed from position statement. Description, Rationale, Background, Definition, and Reference sections updated.

Revised

05/09/2013

MPTAC review.

Revised

05/08/2013

Hematology/Oncology Subcommittee review. Position statement updated to include “Molecular Intelligence Service”. Description, Rationale, Background, Definition, Reference, and Index Sections updated.

 

01/01/2013

Updated Coding section with 01/01/2013 CPT changes; removed 88384-88386 deleted 12/31/2012.

New

05/10/2012

MPTAC review.

New

05/09/2012

Hematology/Oncology Subcommittee review. Initial document development.