Coding Code Description CPT
0017U Oncology (hematolymphoid neoplasia), JAK2 mutation, DNA, PCR amplification of exons 12 – 14 and sequence analysis, blood or bone marrow, report of JAK2 mutation not detected or detected
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
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
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
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
Medical studies have shown that doing specific genetic tests on certain tumors is useful in choosing which treatment to use. These genetic tests look for the presence or absence of known genetic changes.
The results can be used to match a person to the therapy that will be most helpful. There are other types of genetic tests that look at a very large number of genes. These tests are known as expanded molecular panels. They can test hundreds of genes.
The difficulty with expanded molecular panels is that most of the genetic markers tested haven’t been shown to affect either cancer growth or cancer therapies. Because more study is needed, expanded molecular panels are considered investigational.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers.
A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab.This policy informs them about when a service may be covered.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex.
Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing.
Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
There is interest in treating cancers by targeting biologic pathways that are influenced by specific genetic markers. Genetic panel testing offers the potential to evaluate a large number of genetic markers at a single time to identify treatments that target specific pathways.
Some individual markers have established benefit in certain types of cancers; they are not addressed in this medical policy. Rather, this review focuses on “expanded” panels, which are defined as panels that test a wide variety of genetic markers in cancers without regard for whether specific targeted treatment has demonstrated benefit.
This approach may result in a treatment different than that usually selected for a patient based on the type of cancer and stage.
Traditional Therapeutic Approaches to Cancer Tumor location, grade, stage, and the patient’s underly ing physical condition have traditionally been used in clinical oncology to determine the therapeutic approach to a specific cancer, which could include surgical resection, ionizing radiation, systemic chemotherapy, or combinations thereof.
Currently, some 100 different types of tumors are broadly categorized according to the tissue, organ, or body compartment in which they arise. Most treatment approaches in clinical care were developed and evaluated in studies that recruited subjects and categorized results based on this traditional classification scheme.
This traditional approach to cancer treatment does not reflect the wide diversity of cancer at the molecular level. While treatment by organ type, stage, and grade may demonstrate statistically significant therapeutic efficacy overall, only a subgroup of patients may actually derive clinically significant benefit.
It is unusual for a cancer treatment to be effective for all patients treated in a traditional clinical trial. Spear et al analyzed the efficacy of major drugs used to treat several important diseases. They reported heterogeneity of therapeutic responses, noting a low of 25% for cancer chemotherapeutics, with response rates for most drugs falling in the range of 50% to 75%.
The low rate for cancer treatments is indicative of the need for better identification of characteristics associated with treatment response and better targeting of treatment in order to have higher rates of therapeutic responses.
Targeted Cancer Therapy
Much of the variability in clinical response may result from genetic variations. Within each broad type of cancer, there may be a large amount of variability in the genetic underpinnings of the cancer. Targeted cancer treatment refers to the identification of genetic abnormalities present in the cancer of a particular patient, and the use of drugs that target the specific genetic abnormality.
The use of genetic markers allows cancers to be further classified by “pathways” defined at the molecular level. An expanding number of genetic markers have been identified. Dienstmann et al (2013) categorized these markers into 3 classes: 2 ( 1) genetic markers that have a direct impact on care for the specific cancer of interest, (2) genetic markers that may be biologically important but are not currently actionable, and (3) genetic markers of unknown importance.
A small number of individual genetic markers fall into the first category (ie, have established utility for a particular cancer type). The utility of these markers has been demonstrated by randomized controlled trials that select patients with the marker and report significant improvements in outcomes with targeted therapy compared with standard therapy.
This medical policy does not apply to the individual markers that have demonstrated efficacy. According to recent National Comprehensive Cancer Network guidelines,the following markers have demonstrated utility for predicting treatment response to targeted therapies for the specific cancers listed:
o HER2 (ERBB2
oRAS variants(KRAS, NRAS)
Non-small-cell lung cancer (NSCLC):
Chronic myeloid leukemia
Gastrointestinal stromal tumors
Testing for these individual variants with established utility is not addressed in this medical policy.In some cases, limited panels may be offered that are specific to 1 type of cancer (eg, a panel of several markers for NSCLC).
This policy is also not intended to address the use of these cancer
– specific panels that include a few variants. Rather, the intent is to address expanded panels that test for many potential variants that do not have established efficacy for the specific cancer in question.
When advanced cancers are tested with expanded molecular panels, most patients are found to have at least 1 potentially pathogenic variant. The number of variants varies widely by types of cancers, different variants included in testing, and different testing methods among the available studies.
In a 2015 study, 439 patients with diverse cancers were tested with a 236 – gene panel. A total of 1,813 molecular alterations were identified, and almost all patients (420/439 [96%]) had at least 1 molecular alteration. The median number of alterations per patient was 3, and 85% of patients (372/439) had 2 or more alterations. The most common alterations were in the genes TP53 (44%), KRAS (16%), and PIK3CA (12%).
Some evidence is available on the generalizability of targeted treatment based on a specific variant among cancers that originate from different organs. 2,3,7 There are several examples of variant-directed treatment that was effective in 1 type of cancer but ineffective in another.
For example, targeted therapy for epidermal growth factor receptor (EGFR) variants has been successful in NSCLC but not in trials of other cancer types. Treatment with tyrosine kinase inhibitors based on variant testing has been effective for renal cell carcinoma, but has not demonstrated effectiveness for other cancer types tested.
“Basket” studies, in which tumors of various histologic types that share a common genetic variant are treated with a targeted agent, also have been performed. One such study was published in 2015 by Hyman et al.
In this study, 122 patients with BRAF V600 variants in nonmelanoma cancers were treated with vemurafenib.The authors reported that there appeared to be antitumor activity for some but not all cancers, with the most promising results seen for NSCLC, Erdheim-Chester disease, and Langerhans cell histiocytosis.
Summary of Evidence
For individuals who have cancers that have not responded to standard therapy and whose tumors were tested with an expanded cancer molecular panel, the evidence includes a randomized controlled trial, nonrandomized trials, and numerous case series.
Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and other test performance measures. The analytic validity of these panels is likely to be high when next-generation sequencing is used.
The clinical validity of the individual variants for particular types of cancer is not easily obtained from the available published literature. The large number of variants and many different types of cancer preclude determination of clinical validity for the panels as a whole.
Some evidence has reported that many of the identified variants are false positives (ie, not biologically active), after filtering by comparison with matched normal tissue and cancer variant databases. To demonstrate clinical utility, direct evidence from interventional trials, ideally randomized controlled trials, are needed that compare the strategy of targeted treatment based on panel results with standard care.
The first such published randomized controlled trial (the SHIVA trial)reported that there was no difference in progression-free survival when panels were used in this way. Some nonrandomized comparative studies, comparing matched treatment with nonmatched treatment, have reported that outcomes are superior for patients receiving matched treatment.
However, these studies are inadequate to determine treatment efficacy ,because the populations with matched and unmatched cancers may differ on several important clinical and prognostic variables.
Also, there is potential for harm if ineffective therapy is given based on test results, because there may be adverse effects of therapy in absence of a benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.