CAM 20445

Testing for Targeted Therapy of Non-Small-Cell Lung Cancer

Category:Laboratory   Last Reviewed:January 2020
Department(s):Medical Affairs   Next Review:July 2020
Original Date:August 2013    

Description
Non-small cell lung cancer (NSCLC) is a heterogeneous group of cancers encompassing any type of epithelial lung cancer other than small cell lung cancer (SCLC) which arise from the epithelial cells of the lung and include squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. NSCLCs are associated with cigarette smoke; however, adenocarcinomas may be found in patients who have never smoked (Alberg, Ford, & Samet, 2007). Recently, oncogenesis in NSCLC has been associated with mutations in the epidermal growth factor receptor (EGFR) or rearrangements of the anaplastic lymphoma kinase (ALK) gene or ROS1 gene (Sequist & Neal, 2017).

Background
Primary lung cancer remains the most common malignancy after non-melanocytic skin cancer, and deaths from lung cancer exceed those from any other malignancy worldwide. Non-small cell lung cancers (NSCLCs) account for 85%–90% of lung cancers, while small-cell lung cancer (SCLC) has been decreasing in frequency in many countries over the past two decades (Jemal et al., 2011).

An improved understanding of the molecular and immune pathways that drive malignancy in NSCLC, as well as other neoplasms, most notably mutations in the epidermal growth factor receptor (EGFR) or rearrangements of the anaplastic lymphoma kinase (ALK) gene or ROS1 gene, has led to the development of specific molecular treatments for patients (L. Sequist & Neal, 2017).

PD-L1 expression testing via immunohistochemistry is used to guide therapy for patients with non-small cell lung cancer. This testing shows that specific antigens are present in tumor tissue. Tumor cells present PD-L1 (programmed death-1 ligand) to T-cells to inhibit the immune response by downregulating cytokine production and T-cell proliferation. Monoclonal antibody therapy (immune therapy) has been developed to inhibit this pathway and allow for the body’s own immune system, in patients with higher levels of PD-L1 expression, to fight the cancer more effectively.

EGFR - Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are observed in approximately 15 percent of NSCLC adenocarcinoma in the United States and occur more frequently in nonsmokers (Kawaguchi et al., 2016). In advanced NSCLC, the presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors. (TKIs) such as erlotinib, gefitinib, afatinib, and osimertinib (L. Sequist & Neal, 2017).

ALK - Translocations involving the anaplastic lymphoma kinase (ALK) tyrosine kinase are present in approximately 4 percent of NSCLC adenocarcinoma in the United States and occur more frequently in nonsmokers and younger patients. In advanced-stage NSCLC, the presence of an ALK translocation strongly predicts for sensitivity to ALK TKIs (e.g., crizotinib, ceritinib, alectinib) (L. Sequist & Neal, 2017).

ROS1 - is a receptor tyrosine kinase that acts as a driver oncogene in 1 to 2 percent of NSCLC via a genetic translocation between ROS1 and other genes, the most common of which is CD74 (Bergethon et al., 2012). Histologic and clinical features that are associated with ROS1 translocations include adenocarcinoma histology, younger patients, and never-smokers. The ROS1 tyrosine kinase is highly sensitive to crizotinib due to a high degree of homology between the ALK and ROS tyrosine kinase domains (L. Sequist & Neal, 2017).

HER2 HER2 (ERBB2) is an EGFR family receptor tyrosine kinase. Mutations in HER2 have been detected in approximately 1 to 2 percent of NSCLC tumors (Arcila et al., 2012). They usually involve small in-frame insertions in exon 20, but point mutations in exon 20 have also been observed. These tumors are predominantly adenocarcinomas, are more prevalent among never-smokers, and a majority of these patients are women. There is no obvious association between HER2 amplification and HER2 mutations, and previous trials demonstrated no benefit for trastuzumab in HER2-amplified NSCLC, this testing is not recommended in NSCLC (L. Sequist & Neal, 2017; Zinner et al., 2004).

BRAF mutation — BRAF is a downstream signaling mediator of KRAS that activates the mitogen-activated protein kinase (MAPK) pathway. Activating BRAF mutations have been observed in 1 to 3 percent of NSCLC and are usually associated with a history of smoking (L. V. Sequist, Heist et al., 2011). BRAF inhibition with oral small-molecule TKIs (e.g., vemurafenib and dabrafenib) appears to be an effective strategy in the treatment of progressive BRAF V600-mutant NSCLC (L. Sequist & Neal, 2017).

MET abnormalities — MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF). MET abnormalities include MET exon 14 skipping mutations (in 3 percent of lung adenocarcinomas and up to 20 percent of pulmonary sarcomatoid carcinomas), MET gene amplification (in 2 to 4 percent of treatment naïve NSCLC), and MET and EGFR co-mutations (in 5 to 20 percent of EGFR-mutated tumors that have acquired resistance to EGFR inhibitors) (Liu et al., 2016; Okuda, Sasaki, Yukiue, Yano, & Fujii, 2008; L. Sequist & Neal, 2017).

RET translocation — The RET gene encodes a cell surface tyrosine kinase receptor that is frequently altered in medullary thyroid cancer. Recurrent translocations between RET and various fusion partners (CCDC6, KIF5B, NCOA4) have been identified in 1 to 2 percent of adenocarcinomas, and occur more frequently in younger patients and in never-smokers (L. Sequist & Neal, 2017; Takeuchi et al., 2012; Wang et al., 2012).

RAS mutations — Activating KRAS mutations are observed in approximately 20 to 25 percent of lung adenocarcinomas in the United States, and are generally associated with smoking (O'Byrne et al., 2011). The presence of a KRAS mutation appears to have at most a limited effect on overall survival in patients with early-stage NSCLC (Shepherd et al., 2013), although some older data had suggested that it was associated with a worse prognosis (Mascaux et al., 2005). NRAS is homologous to KRAS, associated with smoking, and mutations have been observed in approximately 1 percent of NSCLC (L. V. Sequist, Heist et al., 2011). The clinical significance of NRAS mutations is unclear, and no effective targeted therapies have been identified (L. Sequist & Neal, 2017).

PIK3CA, AKT1, PTEN alterations — PIK3CA encodes the catalytic subunit of phosphatidyl 3-kinase (PI3K), which is an intracellular central mediator of cell survival signals. AKT1 acts immediately downstream of PI3K. Phosphatase and tensin homolog (PTEN) inhibits AKT by dephosphorylation. Oncogenic alterations in this pathway, which occur more frequently in tumors of squamous histology and smokers, include gain-of-function mutations in PIK3CA and AKT1, and loss of PTEN function (Jin et al., 2010; Lee et al., 2010). PIK3CA mutations may also promote resistance to EGFR TKIs in EGFR-mutant NSCLC (L. V. Sequist, Waltman et al., 2011). Small-molecule inhibitors of PI3Kinase and AKT are in clinical development and hold particular hope for the treatment of squamous cell lung cancer. However, since these alterations often overlap with other molecular changes, they may represent a "passenger" mutation rather than a "driver" alteration, and therefore clinical efficacy of these agents against specific molecular alterations is unknown.

Precision oncology is now the evidence-based standard of care for the management of many advanced NSCLCs. Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents (Shea, Costa, & Rangachari, 2016).  

Policy

  1. Testing for EGFR and BRAF mutations, ALK and ROS1 rearrangements is considered MEDICALLY NECESSARY before any systemic therapy initiation in patients with lung cancer.
  2. Multiplexed genetic sequencing panels testing including BRAF, MET, RET, ERBB2(HER2), KRAS is considered MEDICALLY NECESSARY to identify other treatment options beyond EGFR, ALK, and ROS1 in patients with lung cancer
  3. Analysis of PD-L1 expression by immunohistochemistry in Non-Small Cell Lung Cancer tumors is considered MEDICALLY NECESSARY  before first-line therapy with pembrolizumab in patients with metastatic disease meeting one of the following:,
    1. Individuals with adenocarcinoma, large cell, or not otherwise specified NSCLC or
    2. Individuals with squamous cell carcinoma who have never smoked or
    3. Individuals with mixed histology or
    4. When the biopsy specimen is small.
  4. Testing for NTRK gene fusion is considered MEDICALLY NECESSARY for individuals with metastatic or advanced NSCLC before first-line or subsequent therapy with larotrectinib or entrectinib.
  5. Tumor mutational burden (TMB) testing is considered MEDICALLY NECESSARY for individuals with metastatic or advanced NSCLC before initiating nivolumab therapy.
  6. Microsatellite instability analysis is considered MEDICALLY NECESSARY for individuals with unresectable or metastatic Non-Small Cell Lung Cancer that has progressed after prior treatment and for which there is no alternative treatment AND for whom pembrolizumab is being considered for therapy.
  7. KRAS molecular testing is investigational and/or  unproven and therefore considered NOT MEDICALLY NECESSARY as a routine stand-alone assay and as a sole determinant of targeted therapy.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. Analysis of PD-L1 expression by immunohistochemistry in all other situations is considered.is investigational and/or  unproven and therefore considered NOT MEDICALLY NECESSARY.
  2. Analysis for genetic alterations in the genes not mentioned above for targeted therapy in patients with NSCLC is considered is investigational and/or  unproven and therefore considered NOT MEDICALLY NECESSARY. 

NOTE: For more than 5 gene tests being run on a tumor specimen (i.e., non-liquid biopsy) on the same platform, such as multi-gene panel next generation sequencing, please refer to CAM 204115 Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies.

Rationale
PD-L1 receptor expression 
Monoclonal antibody therapy (human immune-checkpoint- inhibitor antibodies that inhibit PD-1 receptors or PD-L1) have been developed to treat individuals with non-small cell lung cancer. The National Comprehensive Cancer Network recommends this testing prior to fist-line treatment with the monoclonal antibody therapy, pembrolizumab. PD-L1 expression is the best biomarker to assess individuals with non-small cell lung cancer for use of the monoclonal antibody therapy, pembrolizumab.

EGFR Gene
The National Comprehensive Cancer Network (NCCN) recommended testing for EGFR mutations of NSCLC tumors that are adenocarcinoma, large cell, or NSCLC not otherwise specified (Category 1). The NCCN also indicates that EGFR mutation testing should be considered in individuals with squamous cell carcinoma, in those who have never smoked, small biopsy specimens, and those with mixed histology (Category 2A).

The 2017 NCCN guidelines on NSCLC stated that gefitinib was recently re-approved by FDA. Erlotinib (category 1), afatinib (category 1), or gefitinib (category 1) are recommended as first-line systemic therapy in patients with sensitizing EGFR mutations.

The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology (CAP/IASLC/AMP) guidelines indicate that "EGFR molecular testing should be used to select patients for EGFR- targeted tyrosine kinase inhibitor therapy (Evidence Grade: A)" (Lindeman et al., 2013). Testing is recommended for adenocarcinomas and mixed lung cancers "regardless of histologic grade." However, in the setting of fully excised lung cancer specimens, EGFR testing is not recommended for lung cancer without any adenocarcinoma component (Evidence Grade: A). In the setting of more limited lung cancer specimens where an adenocarcinoma component cannot be completely excluded, EGFR testing is recommended "in cases showing squamous or small cell histology but clinical criteria (e.g., young age, lack of smoking history) may be useful in selecting a subset of these samples for testing" (Evidence Grade: A).

The American Society of Clinical Oncology (ASCO) recommends testing for EGFR mutations in tumors of NSCLC patients who "are being considered for first-line therapy with an EGFR TKI" to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy (Keedy et al., 2011). In 2014, ASCO endorsed the CAP/IASLC/AMP guidelines and highlighted three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and emergence of other targetable molecular alterations (Leighl et al., 2014).

The package inserts for both erlotinib and afatinib indicate that they are for "first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

ALK Gene
NCCN (v.4.2015) states that ALK rearrangement testing is recommended (category 1) in patients with nonsquamous NSCLC (i.e., adenocarcinoma, large cell carcinoma) or in NSCLC not otherwise specified, because crizotinib (category 1) is recommended for patients who are positive for ALK rearrangements. If ALK-positive status is discovered before first-line chemotherapy, give crizotinib (category 1), or if ALK rearrangement is discovered during first-line chemotherapy, interrupt or complete planned chemotherapy and start crizotinib. If there is progression on crizotinib, NCCN guidelines recommend multiple options (category 2A) including continuing crizotinib, switching to ceritinib, and considering local therapies depending on symptoms.

The 2017 NCCN guidelines (version 5.2017) on NSCLC recommended use of either crizotinib or ceritinib as first-line treatment for ALK-positive metastatic NSCLC (Category 1). The guidelines also state that testing for ALK rearrangements can be considered in patients with squamous cell histology if they are never smokers, or have mixed histology, or when the biopsy specimen is small (Category 2A).

The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines indicate that "ALK molecular testing should be used to select patients for ALK-targeted TKI therapy (Evidence Grade: B)" (Lindeman et al., 2013). Testing is recommended for adenocarcinomas and mixed lung cancers "regardless of histologic grade." However, in the setting of fully excised lung cancer specimens, ALK testing is not recommended for lung cancer without any adenocarcinoma component (Evidence Grade: A). In the setting of more limited lung cancer specimens where an adenocarcinoma component cannot be completely excluded, ALK testing isrecommended "in cases showing squamous or small cell histology but clinical criteria (e.g., young age, lack of smoking history) may be useful in selecting a subset of these samples for testing" (Evidence Grade: A).

KRAS Gene
The National Comprehensive Cancer Network (2017) guidelines note that "EGFR and KRAS mutations are mutually exclusive in patients with lung cancer." As a result, "KRAS mutations are associated with intrinsic TKI resistance, and KRAS gene sequencing could be useful for the selection of patients as candidates for TKI therapy." Overlapping EGFR and KRAS mutations occur in <1% of patients with lung cancer. KRAS mutations are associated with intrinsic TKI resistance, and KRAS gene sequencing could be useful for the selection of patients as candidates for EGFR TKI therapy. KRAS testing may identify patients who may not benefit from further molecular diagnostic testing.

The College of American Pathology does not recommend testing for KRAS mutations in NSCLC samples, and notes that, "KRAS mutation testing is not recommended as a sole determinant of EGFR TKI therapy."

According to the European Society for Medical Oncology (ESMO), genetic alterations, which are key oncogenic events (driver mutations), have been identified in NSCLC, with two of these—EGFR mutations and the anaplastic lymphoma kinase (ALK) rearrangements—determining approved, selective pathway-directed systemic therapy. The ESMO guidelines do not specifically mention KRAS mutation testing (Novello et al., 2016).

ROS1 Gene
In the 2017 guidelines on NSCLC, the NCCN panel recommended testing for ROS1 gene rearrangement for patients with adenocarcinoma, large cell, or NSCLC not otherwise specified (Category 2A). The guidelines also state that testing for ROS1 rearrangements can be considered in patients with squamous cell histology if they are never smokers, or have wmixed histology, or when the biopsy specimen is small (Category 2A). Crizotinib is recommended for patients with ROS1 rearrangements.

Other Genes
NCCN does not give specific recommendations for testing for genetic alterations in the genes RET, MET, BRAF, or HER2 in NSCLC. However, they state that the following targeted agents are now recommended for patients with specific genetic alterations: BRAF V600E mutation: vemurafenib, dabrafenib, dabrafenib + trametinib (category 2A); MET: crizotinib (category 2A); RET rearrangements: cabozantinib, vandetanib (category 2A); HER2 mutations: trastuzumab and afatinib (category 2B).

References

  1. Alberg, A. J., Ford, J. G., & Samet, J. M. (2007). Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest, 132(3 Suppl), 29s-55s. doi:10.1378/chest.07-1347
  2. Arcila, M. E., Chaft, J. E., Nafa, K., Roy-Chowdhuri, S., Lau, C., Zaidinski, M., . . . Ladanyi, M. (2012). Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res, 18(18), 4910-4918. doi:10.1158/1078-0432.ccr-12-0912
  3. Bergethon, K., Shaw, A. T., Ou, S. H., Katayama, R., Lovly, C. M., McDonald, N. T., . . . Iafrate, A. J. (2012). ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol, 30(8), 863-870. doi:10.1200/jco.2011.35.6345
  4. Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA Cancer J Clin, 61(2), 69-90. doi:10.3322/caac.20107
  5. Jin, G., Kim, M. J., Jeon, H. S., Choi, J. E., Kim, D. S., Lee, E. B., . . . Park, J. Y. (2010). PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer, 69(3), 279-283. doi:10.1016/j.lungcan.2009.11.012
  6. Kawaguchi, T., Koh, Y., Ando, M., Ito, N., Takeo, S., Adachi, H., . . . Matsumura, A. (2016). Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study. J Clin Oncol, 34(19), 2247-2257. doi:10.1200/jco.2015.64.2322
  7. Le, D., Uram, J., Wang, H., Barlett, B., Kemberling, H., Eyring, A.,… Diaz., L.. (2015). PD-1 Blockade in tumors with mismatch-repair deficiency. Retrieved June 13, 2017, from http://www.nejm.org/doi/full/10.1056/NEJMoa1500596#t=abstract
  8. Lee, S. Y., Kim, M. J., Jin, G., Yoo, S. S., Park, J. Y., Choi, J. E., . . . Jung, T. H. (2010). Somatic mutations in epidermal growth factor receptor signaling pathway genes in non-small cell lung cancers. J Thorac Oncol, 5(11), 1734-1740. doi:10.1097/JTO.0b013e3181f0beca
  9. Lindeman, N. I., Cagle, P. T., Beasley, M. B., Chitale, D. A., Dacic, S., Giaccone, G., … Ladanyi, M. (2013). Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Archives of Pathology & Laboratory Medicine, 137(6), 828–860. http://doi.org/10.5858/arpa.2012-0720-OA
  10. Leighl, N. B., Rekhtman, N., Biermann, W. A., Huang, J., Mino-Kenudson, M., Ramalingam, S. S., … Somerfield, M. R. (2014). Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Journal of Clinical Oncology, 32(32), 3673–3679. http://doi.org/10.1200/JCO.2014.57.3055
  11. Liu, X., Jia, Y., Stoopler, M. B., Shen, Y., Cheng, H., Chen, J., . . . Borczuk, A. C. (2016). Next-Generation Sequencing of Pulmonary Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations. J Clin Oncol, 34(8), 794-802. doi:10.1200/jco.2015.62.0674
  12. National Comprehensive Cancer Guidelines. (2017). Non-small cell lung cancer. Retrieved June 13, 2017, from https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  13. Mascaux, C., Iannino, N., Martin, B., Paesmans, M., Berghmans, T., Dusart, M., . . . Sculier, J. P. (2005). The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer, 92(1), 131-139. doi:10.1038/sj.bjc.6602258
  14. Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M. G., . . . Peters, S. (2016). ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.; 27(suppl 5): v1-v27.DOI:10.1093/annonc/mdw326
  15. O'Byrne, K. J., Gatzemeier, U., Bondarenko, I., Barrios, C., Eschbach, C., Martens, U. M., . . . Pirker, R. (2011). Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol, 12(8), 795-805. doi:10.1016/s1470-2045(11)70189-9
  16. Okuda, K., Sasaki, H., Yukiue, H., Yano, M., & Fujii, Y. (2008). Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci, 99(11), 2280-2285. doi:10.1111/j.1349-7006.2008.00916.x
  17. Sequist, L., & Neal, J. (2017). Personalized, genotype-directed therapy for advanced non-small cell lung cancer - UpToDate. In S. Vora (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer?source=search_result&search=kras%20non%20small%20cell%20lung&selectedTitle=6~150.
  18. Sequist, L. V., Heist, R. S., Shaw, A. T., Fidias, P., Rosovsky, R., Temel, J. S., . . . Dias-Santagata, D. (2011). Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol, 22(12), 2616-2624. doi:10.1093/annonc/mdr489
  19. Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., . . . Engelman, J. A. (2011). Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med, 3(75), 75ra26. doi:10.1126/scitranslmed.3002003
  20. Shea, M., Costa, D. B., & Rangachari, D. (2016). Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis, 10(2), 113-129. doi:10.1177/1753465815617871
  21. Shepherd, F. A., Domerg, C., Hainaut, P., Janne, P. A., Pignon, J. P., Graziano, S., . . . Tsao, M. S. (2013). Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol, 31(17), 2173-2181. doi:10.1200/jco.2012.48.1390
  22. Takeuchi, K., Soda, M., Togashi, Y., Suzuki, R., Sakata, S., Hatano, S., . . . Ishikawa, Y. (2012). RET, ROS1 and ALK fusions in lung cancer. Nat Med, 18(3), 378-381. doi:10.1038/nm.2658
  23. U.S. Food and Drug Administration. (2010). FDA approves first cancer treatment for any solid tumor with a specific genetic feature. Retrieved June 13, 2017, from https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm
  24. Wang, R., Hu, H., Pan, Y., Li, Y., Ye, T., Li, C., . . . Chen, H. (2012). RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol, 30(35), 4352-4359. doi:10.1200/jco.2012.44.1477
  25. Zinner, R. G., Glisson, B. S., Fossella, F. V., Pisters, K. M., Kies, M. S., Lee, P. M., . . . Herbst, R. S. (2004). Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease. Lung Cancer, 44(1), 99-110. doi:10.1016/j.lungcan.2003.09.026

 Coding Section

Codes Number Description
CPT 81210  BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
  81235 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion L858R, T790M, G719A, G719S, L861Q)
  81275  KRAS (eg carcinoma) gene analysis, variants in codons 12 and 13 
  81276  KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma gene analysis; additional variants(s) (eg, codon 61, codon 146) 
  81301  Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed 
  81401  Molecular pathology proc, level 2 
  81404  Molecular pathology proc, level 5
  88271

Molecular cytogenetics; DNA probe, each (eg, FISH) 

  88272 Molecular cytogenetics; chromosomal in situ hybridization, analyze 3-5 cells (eg, for derivatives and markers) 
  88273 Molecular cytogenetics; chromosomal in situ hybridization, analyze 10-30 cells (eg, for microdeletions) 
  88342 Immunohistochemistry or immunocytochemistry, per specimen; each multiplex antibody stain procedure 
  88360 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual 
  88361 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; using computer-assisted technology 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

01/06/2020 

Interim review to add statement regarding entrectinib to medical necessity. Also updating coding. 

07/22/2019 

Annual review, updating policy with medical necessity verbiage for NTRK and TMB testing, no other change to policy intent. Updating coding. 

08/06/2018 

Annual review, rewriting policy verbiage for clarity and expansion of coverage, removing gene-specific criteria. 

04/30/2018 

Updated Next Review Date. No change to policy intent 

12/12/2017 

Interim review with expanded medically necessary indications. Reformatting policy for clarity. 

04/11/2017 

Annual review, no change to policy intent. 

10/03/2016 

Interim review, updating medical necessity criteria for EGFR testing. 

04/19/2016

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

01/04/2016 

Updated CPT coding. No change in policy intent. 

04/30/2015 

Annual review, no change to policy intent. Updated background, description, regulatory status, related policies, rationale and references. Added coding. 

04/01/2014

Added medically necesary statement for afatinib. Updated description, background, related policies, guidelines, rationale and references. Added FDA status.  


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