Clinical Policy: Her2/neu Testing Reference Number: CP.MP.155

Transcription

1 Clinical Policy: Her2/neu Testing Reference Number: CP.MP.155 Effective Date: June 2004 Last Review Date: June 2017 Coding Implications Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Human epidermal growth factor receptor 2 testing (Her2/neu) is used to provide prognostic information regarding response to chemotherapy (including Herceptin) for newly diagnosed invasive breast cancers and first recurrences of breast cancer, based on recommendations from the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). Policy/Criteria I. It is the policy of Health Net of California to consider human epidermal growth factor receptor 2 testing (Her2/neu) medically necessary for all newly diagnosed patients with breast cancer as well as those who then develop metastatic disease should have HER2 testing performed in a metastatic site, if tissue sample is available. The level of expression may be used to provide prognostic information regarding response to chemotherapy based on the following: A. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of FDA approved IHC, Brightfield in-situ hybridization (ISH), or FISH assay is proposed; and B. Elements to reduce assay variation (Eg. specimen handling, assay exclusion, and reporting criteria) are specified; and C. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended. This means: 1. A positive HER2 result is IHC 3+ based on circumferential membrane staining that is complete and intense; or fluorescent in situ hybridization (FISH) result based on: a. Single-probe average HER2 copy number of >6.0 signals/cell; b. Dual-probe of HER2/CEP17 ratio >2.0 with average HER2 copy number >4.0 signals/cell; c. Dual-probe of HER2/CEP17 ratio >2.0 with an average HER2 copy number <4.0 signals/cell; d. Dual-probe of HER2/CEP17 ratio <2.0 with an average HER2 copy number >6.0 signals/cell. 2. Must report HER2 test result as equivocal and order reflex test (same specimen using the alternative test) or new test (new specimen, if available, using same or alternative test) based on: a. IHC 2+ based on circumferential membrane staining that is incomplete and/or weak/moderate and within >10% of the invasive tumor cells; or Page 1 of 12

2 complete and circumferential membrane staining that is intense and within 10% of the invasive tumor cells b. ISH equivocal based on: Single-probe ISH average HER2 copy number 4.0 and <6.0 signals/cell, Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number 4.0 and <6.0 signals/cell. 3. Must report a HER2 test result as negative if a single test (or both tests) performed show: a. IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within >10% of the invasive tumor cells b. IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within 10% of the invasive tumor cells c. ISH negative based on: Single-probe average HER2 copy number <4.0 signals/cell, Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number <4.0 signals/cell 4. Must report HER2 test result as indeterminate if technical issues prevent one or both tests (IHC and ISH) from being reported as positive, negative, or equivocal. Conditions may include: a. Inadequate specimen handling b. Artifacts (crush or edge artifacts) that make interpretation difficult c. Analytic testing failure. Another specimen should be requested for testing to determine HER2 status. Reason for indeterminate testing should be noted in a comment in the report. II. It is the policy of Health Net of California to consider testing of tumor HER2-neu overexpression using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) medically necessary in individuals with inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach, esophagus or esophagogastric (GE) junction. Traustuzumab should be added to chemotherapy for HER2-neu overexpressing metastatic adenocarcinoma. Background The HER-2 gene normally produces a protein called HER-2 (human epidermal growth factor receptor). This protein is responsible for growth and division of cells. In 25-30% of women with metastatic breast cancer and in varying degrees in colorectal, gastric, ovarian, pancreatic, cervical, and prostate cancers, there is a genetic alteration in the Her2/neu gene causing an increased amount of overexpression of this protein. Overexpression of her2/neu leads to unregulated cell growth and may cause transformation of cells in malignancy. The overproduction of this protein is associated with a more aggressive disease and a shortened survival as the tumor is generally resistant to chemotherapy. Page 2 of 12

3 Her2/neu is used a predictor of response to therapy, such as hormone therapy and chemotherapy. If the level is initially elevated then falls, it is likely that treatment is effective. If it remains elevated, the treatment is effective; and if the level falls then rises, the cancer may be recurring. Two distinct methods are used for detection of the HER-2/neu oncogene in breast and gastric cancer patients. Both methods can be performed on archived or current specimens. IHC (ImmunoHistoChemistry) The IHC test uses specific antibodies to measure the protein excreted by the HER2gene. A tissue sample is taken during biopsy or surgery and a slide is prepared from the tumor block. It is then stained and the result of the test is reported as 0, 1+, 2+, or 3+. If a tumor is scored at a level 2+ or 3+, it is considered positive. Tumors with IHC 2+ scores are considered borderline though a few patients with level 2 over expression will benefit from Herceptin. Tumors with a 3+ score from an IHC test are distinctly positive, and many patients at this level would benefit from Herceptin therapy. The IHC HercepTest (DAKO, Glostrup, Denmark) and the IHC Pathway HER2 test (Ventana Medical Systems, Tucson, AZ) have FDA approval for determining the HER2 status of breast cancer tumors. FISH (Fluorescent in situ hybridization) Assay FISH evaluates the genetic level for gene amplification using a DNA probe that binds to the actual HER-2 gene. The gene can be directly visualized and the number of Her-2 neu genes per tumor cell can be quantified. The FISH test, which can be done on new or old tumor tissue samples, is considered the most accurate test for HER2/neu gene malfunction. It is the preferred method for testing older tissue either positive or negative. An example of this type of test is the PathVysion HER- 2 DNA Probe Kit. This test is intended for use as an adjunct to existing clinical and pathological information currently used as prognostic factors in stage II, node positive breast cancer patients. It is also indicated for use as an aid to predict disease free and over-all survival in patients with stage II, node positive breast cancer treated with adjuvant cyclophosphamide, doxorubicin and 5-fluorouracid (CAF) chemotherapy. Normally, there should be two chromosome, 17 signals and two HER-2 gene signals. This indicates a ratio of 1:1, meaning there is one HER-2 signal for each chromosome 17 signal, which is a normal result. However, when the ration is greater than 2:1, this means there are more than one HER-2 signal for each chromosome 17. This means that the HER-2 gene is amplified, which is abnormal. Recent data from large retrospective studies in breast cancer patients have revealed that survival results for women with Her-2/neu overexpression in the absence of Her-2/neu gene amplification is statistically indistinguishable from patients who are negative with both techniques. A positive FISH results by itself, with or without IHC corroboration, is a significantly better discriminator of adverse prognosis. Page 3 of 12

4 NCCN Panel on Breast Cancer agrees with the ASCO/CAP HER2 committee that this is the appropriate protocol with equivocal HER2 results. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, labs show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document. (Arch Pathology Lab Med. 2007) The American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) recently convened an Update Committee to conduct a systematic literature review and update recommendations for optimal HER2 testing. The Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). In 2013, the guideline was reviewed and approved by both organizations and has been published jointly by invitation and consent in both the Journal of Clinical Oncology and the Archives of Pathology & Laboratory. The panel recommended HER2 status should always be tested for on all newly diagnosed invasive breast cancers (primary site and/or metastatic site) and that at least one tumor sample is tested for either HER2 protein expression (immunohistochemistry [IHC] assay) or (in situ hybridization [ISH assay]) for HER2 gene amplification. Among the recommendations is that the role of HER2-targeted therapy should be discussed when the HER2 test result is positive and if there is no apparent histopathologic discordance with HER2 testing. The decision to recommend HER2-targeted therapy should be delayed if the HER2 test result is equivocal, once a mandatory retest using an alternative test is performed. It is also important to ensure that the testing laboratory conforms to standards to ensure accurate results. The 2017 National Comprehensive Cancer Network (NCCN) Practice Guidelines in Oncology for Breast Cancer also recommend determination of HER2 status for all newly diagnosed invasive breast cancers. They state that HER2 status can be assessed by measuring the number of HER2 gene copies (FISH assay) or by a complementary method in which the number of HER2 cell surface receptors is evaluated (IHC assay). The NCCN Breast Cancer Panel recommends selecting patients for trastuzumab (Herceptin) therapy who have tumors either positive for HER2 by FISH, or 3+ by IHC. Patients with tumors IHC 0, or 1+ for HER2, or FISH not amplified have very low rates of trastuzumab response and therefore therapy with trastuzumab is not warranted.. The NCCN panel endorses the use of College of American Pathologists protocols for reporting the pathological analysis of all breast specimens. In the 2011 NCCN 2011 Gastric Cancer Practice Guidelines, a randomized, prospective, multicenter, phase III trial was reported that evaluated the efficacy and safety of trastuzumab in HER2-positive gastric cancer in combination with cisplatin and a fluoropyrimidine. The results Page 4 of 12

5 of this study confirmed that trastuzumab plus standard chemotherapy is superior in improving median overall survival to chemotherapy alone in patients with HER2-positive advanced gastric cancer, with no unexpected adverse. Coding Implications This clinical policy references Current Procedural Terminology (CPT ). CPT is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2015, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. ICD-10 Codes Description C15.3-C15.8 Malignant neoplasm of esophagus stoma C16.0-C16.8 Malignant neoplasm of stomach C C Malignant neoplasm of breast C78.7-C78.89 Secondary malignant neoplasm of other digestive organs Z85.3 Personal history neoplasm of the breast HCPCS Codes Description CPT Description Codes Serum assay, Oncoprotein (HER2/neu microtiter ELISA) Molecular cytogenetics: DNA probe, each (eg FISH) Molecular cytogenetics: Interphase in situ hybridization, analyze cells Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (list separately in addition to code for primary procedure) Immunocytochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure (Code revised in 2015) Immunohistochemistry or immunocytochemistry, per specimen; each multiplex antibody stain procedure Morphometric analysis, tumor immunohistochemistry (e.g. HER-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual using computer-assisted technology In situ hybridization (e.g., FISH), per specimen; each additional single probe Page 5 of 12

6 CPT Description Codes stain procedure (list separately in addition to code for primary procedure) Tissue in situ hybridization, (eg. FISH) per specimen; initial single probe stain procedure (Code revised in 2015) Morphometric analysis, in situ hybridization (quanitative or semiquantitative) using computer-assisted technology, per specimen; initial single probe stain procedure (Code revised in 2015) Morphometric analysis, in situ hybridization (quanitative or semiquantitative), manual, per specimen; initial single probe stain procedure (Code revised in 2015) Morphometric analysis, in situ hybridization, (quantitative or semiquantitative), manual, per specimen; each additional single probe stain procedure (list separately in addition to code for primary procedure) Morphometric analysis, in situ hybridization, (quantitative or semiquantitative), using computer-assisted technology, per specimen; each additional single probe stain procedure (list separately in addition to code for primary procedure) Reviews, Revisions, and Approvals Date Approval Date Initial Approval 6/04 Update. Removed requirement that Herceptin is indicated only for 6/06 Stage IV metastatic breast cancer Update. Codes Reviewed. Revisions- added 2008 FDA indication for 3/08 Herceptin dosage. Added 2007 American Society of Clinical Oncology / College of American Pathologists guideline recommendations for HER2 testing in invasive breast cancer Changed policy name to Her2/neu. Removed criteria for Herceptin from the 6/08 policy statement. Removed section on current protocol of Herceptin administration from scientific rationale Based on recommendations from the NCCN and the US FDA, updated 6/11 policy to include testing of tumor HER2-neu overexpression using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) as medically necessary in individuals with inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach, esophagus or esophagogastric (GE) junction when traustuzumab therapy is being considered Update. Added definition of equivocal HER2 results. Added NCCN 2013 breast cancer recommendation that 2+ expression of HER2neu by IHC should be additionally examined by FISH or other in situ hybridization methods. Codes updated. 6/13 Page 6 of 12

7 Reviews, Revisions, and Approvals Date Approval Date Update. Added updated information from the College of American 6/14 Pathology (CAP) to #3 in the Policy Statement. Codes updated Added additional information to policy statement from NCCN regarding 6/15 equivocal HER2 results and added information regarding 2+ and 3+ HER2 neu status. Codes updated. Added updated CAP, ASCO and NCCN guidelines to algorithms to clarify 6/16 positive, equivocal, negative and indeterminate HER2 results. Added HER2/neu testing is medically necessary for first recurrences of breast cancer, whenever possible. Added Traustuzumab should be added to chemotherapy for HER2-neu overexpressing of esophageal and esophagogastric metastatic adenocarcinoma. Codes upated. Codes updated 6/17 References 1. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology, College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007 Jan 1;25(1): Updated November ng_guidelines.pdf 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Esphoageal and Esophagogastric Junction Cancers. Version Update Version Updated Version Updated Version Update Version 1, National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Gastric Cancer. Version Update Version Updated Version Update Version Update Version National Comprehensive Cancer Network. NCCN Clinical Practice of Oncology. Breast Cancer. Version Update Version Update Version Updated Version Updated Version Update Version Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. Adv Anat Pathol 2011; 18: Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: Bouché O, Penault-Llorca F. HER2 and gastric cancer: a novel therapeutic target for trastuzumab. Bull Cancer Dec;97(12): Burstein H. Adjuvant medical therapy for HER2-positive breast cancer. UpToDate. February 9, Page 7 of 12

8 9. Cochrane DR, Bernales S, Jacobsen BM, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res 2014; 16:R Croxtall JD, McKeage K. Trastuzumab: in HER2-positive metastatic gastric cancer. Drugs Dec 3;70(17): De Vita F, Giuliani F, Silvestris N, et al. Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target. Cancer Treat Rev Nov;36 Suppl 3:S Di Leo A, Desmedt C, Bartlett JM, et al. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol 2011; 12: Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 2014; 106:djt Ellis PA, Barrios CH, Eirmann W, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. ASCO Annual Meeting (May 29 - June 2, 2015). Vol 33, No 15_suppl (May 20 Supplement), 2015: American Society of Clinical Oncology. 15. Fabi A, Di Benedetto A, Metro G, et al. HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care. Clin Cancer Res 2011; 17: Fan YS, Casas CE, Peng J, et al. HER2 FISH classification of equivocal HER2 IHC breast cancers with use of the 2013 ASCO/CAP practice guideline. Breast Cancer Res Treat Feb;155(3): doi: /s z. Epub 2016 Feb Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16: Glynn RW, Mahon S, Curran C, et al. TOP2A amplification in the absence of that of HER-2/neu: toward individualization of chemotherapeutic practice in breast cancer. Oncologist 2011; 16: Goldhirsch A, Picart-Gebhart M, Proctor M, et al. HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. Cancer Research: December 15, 2012; Volume 72, Issue 24, Supplement 3. doi: / SABCS12-S Hammond ME, Hayes DF, Wolff AC. Clinical Notice for American Society of Clinical Oncology-College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol 2011; 29:e Hayes DF. Steady progress against HER2-positive breast cancer. N Engl J Med 2011; 365: Hechtman JF, Polydorides AD. HER2/neu gene amplification and protein overexpression in gastric and gastroesophageal junction adenocarcinoma: a review of histopathology, diagnostic testing, and clinical implications. Arch Pathol Lab Med Jun;136(6): doi: /arpa RS. Page 8 of 12

9 23. Kovács A, Stenman G. HER2-testing in 538 consecutive breast cancer cases using FISH and immunohistochemistry. Pathol Res Pract Jan 15;206(1): Leyland-Jones B, Smith BR. Serum HER2 testing in patients with HER2-positive breast cancer: the death knell tolls. Lancet Oncol 2011; 12: Lindstrom LS, Karlsson E, Wilking LM, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol Jul 20; 30(21): doi: /JCO Epub 2012 Jun Lordick F. Trastuzumab: a new treatment option for HER2-positive metastatic gastric and gastroesophageal junction cancer. Future Oncol Feb;7(2): Lorenzen S, Lordick F. How will human epidermal growth factor receptor 2-neu data impact clinical management of gastric cancer? Curr Opin Oncol Apr Muller KE, Marotti JD, Memoli VA. et al. Impact of the 2013 ASCO/CAP HER2 Guideline Updates at an Academic Medical Center That Performs Primary HER2 FISH Testing: Increase in Equivocal Results and Utility of Reflex Immunohistochemistry. Am J Clin Pathol Aug;144(2): O'Sullivan CC, Swain SM. Pertuzumab: Evolving therapeutic strategies in the management of HER2-overexpressing breast cancer. Expert Opin Biol Ther. 2013;13(5): Papouchado BG, Myles J, Lloyd RV, et al. Silver In Situ Hybridization (SISH) For Determination of HER2 Gene Status in Breast Carcinoma: Comparison With FISH and Assessment of Interobserver Reproducibility. Am J Surg Pathol Apr Pennacchia I, Carbone A, Di Cerbo A, et al ASCO/CAP updated guidelines for human epidermal growth factor receptor 2 testing: Impact on routine practice. Breast Jun;24(3): doi: /j.breast Epub 2015 Feb Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG tran9831. J Clin Oncol 2014; 32: Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormonereceptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol 2014; 25: Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-her2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol 32:5s, Available at: Press, M.F., et al. Evaluation of HER-2/neu Gene Amplification and Overexpression: Comparison of Frequently Used Assay Methods in a Molecularly Characterized Cohort of Breast Cancer Specimens. Journal of Clinical Oncology. July 15, 2002; 20(14): Riethdorf S, Hoegel B, John B, et al. Prospective multi-centre study to validate chromogenic in situ hybridisation for the assessment of HER2 gene amplification in Page 9 of 12

10 specimens from adjuvant and metastatic breast cancer patients. J Cancer Res Clin Oncol Apr Robertson JF, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the phase II first study San Antonio Breast Cancer Symposium; 38. What is different in comparison to breast cancer?. Pathologe May;31(3): Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9): Semiglazov VF, Bozhok AA, Semiglazova, et al. HER2-positive breast cancer: Standard and double targeted therapy. Vopr Onkol. 2013;59(3): Singh K, Tantravahi U, Lomme MM, et al. Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers. Breast Cancer Res Treat May 14. [Epub ahead of print] 42. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365: Summary of ASCO/CAP HER2 Guideline Recommendations. Optimal tissue handling requirements. Revised per the 2011 ASCO/CAP Clinical Notice on HER2 and ER/PgR. Available at: ndations.pdf 44. Thompson SK, Sullivan TR, Davies R, Ruszkiewicz AR. HER-2/neu Gene Amplification in Esophageal Adenocarcinoma and Its Influence on Survival. Ann Surg Oncol Jan Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for nodenegative, HER2-positive breast cancer. N Engl J Med Jan 8;372(2): doi: /NEJMoa Varga S, Noske A. Impact of Modified 2013 ASCO/CAP Guidelines on HER2 Testing in Breast Cancer. One Year Experience. PLoS One. 2015; 10(10): 2015 Oct Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med Nov 8; 367 (19): doi: /NEJMoa Epub 2012 Oct Yamauchi H, Hayes DF. HER2 and predicting response to therapy in breast cancer. UpToDate. January Updated October Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program Page 10 of 12

11 approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. Health Plan means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services. Page 11 of 12

12 Note: For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy. Note: For Medicare members, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs, LCDs, and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at for additional information Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation. Page 12 of 12