CAM 20436

Gene Expression Testing for Breast Cancer Prognosis

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:July 2004    

Description: 
Gene expression assays measure the amount of specific mRNAs being transcribed to assess the genes that are active in a particular cell or tissue. Analyses of gene expression can be clinically useful for disease classification, diagnosis, prognosis, and tailoring treatment to underlying genetic determinants of pharmacologic response (Spira, 2017).

Adjuvant systemic therapy has reduced mortality from breast cancer (Davies et al., 2011; Peto et al., 2012). Several breast tumor gene expression assays have been developed to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer (Harris et al., 2016; Theodoros & Bergh, 2017). 

Globally, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women. In the United States, breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer death in women. Approximately 1 in 8 women will develop breast cancer in their lifetime (Taghian, El-Ghamry, & Merajver, 2017).

Adjuvant systemic therapy has reduced mortality from breast cancer (Darby et al., 2011; Davies et al., 2011; Forouzanfar et al., 2011; Peto et al., 2012). However, adjuvant therapy is not without its risks and costs, reliable prognostic for recurrence and clinically applicable predictive factors would be of great value in the use of adjuvant therapy by identifying which therapies would be most likely of benefit to patients and which patients would not benefit(Theodoros & Bergh, 2017).

Several biology-based prognostic profiles have been developed, validated, and are in clinical use to predict breast cancer response to chemotherapy. Intensive research efforts are ongoing to refine the clinical utility and the indications for these prognostic profiles (Simon, Paik, & Hayes, 2009). In addition, as next generation sequencing of tumor genomes progresses, these profiles will be improved or replaced by the next generation of molecular profiles (Banerji et al., 2012; CGAN, 2012; Curtis et al., 2012; Ding et al., 2010; Ellis et al., 2012; Shah et al., 2012; Theodoros & Bergh, 2017)

The Oncotype Dx 21-gene recurrence score (RS) is the best-validated prognostic assay and may identify patients who are most and least likely to derive benefit from adjuvant chemotherapy. The expression levels of 16 genes (plus five reference genes) are measured by quantitative reverse transcription polymerase chain reaction (RT-PCR). The sum of this calculation is known as the RS to optimize prediction of distant relapse despite tamoxifen therapy. At this time, it is indicated for women with node-negative, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer to determine the prognosis in patients recommended to proceed with at least a five-year course of endocrine therapy. The optimal RS cutoff for omission of chemotherapy remains unclear given that the different studies have used different cutoffs (Mamounas et al., 2010; Paik et al., 2004; Paik et al., 2006; Sparano et al., 2015). However, it is reasonable not to administer adjuvant chemotherapy for patients with node-negative, ER-positive breast cancer and an RS of <18 (Theodoros & Bergh, 2017).

Sparano et al (2018) performed a prospective trial to assess the utility of the recurrence score based on the 21 gene breast cancer assay to predict chemotherapy in patients who have a midrange score. "Of the 9,719 eligible patients with follow-up information, 6,711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death)." They found that "Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25." They concluded that "Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger."

EndoPredict (EP) utilizes reverse transcriptase polymerase chain reaction (PCR) of 11 genes (including three reference genes) to calculate a prognostic score. EP appears to be useful in the identification of a subgroup of patients with ER-positive, HER2-negative tumors that have a very low risk of recurrence without adjuvant chemotherapy (Dubsky et al., 2013) and appears to identify patients at low risk for a late recurrence (Dubsky et al., 2013; Theodoros & Bergh, 2017).

The Breast Cancer Index (BCI) is a combination of two profiles, the HOXB13-to-IL17BR expression ratio (H:I ratio) and the Molecular Grade Index (MGI). Using genome-wide microarray analysis, three differentially expressed genes that were associated with an increased risk of progression among ER-positive patients treated with tamoxifen were: the antiapoptotic homeobox B13 (HOXB13, overexpressed in tamoxifen recurrent cases) and both interleukin 17B receptor (IL17BR) and EST AI240933 (both overexpressed in tamoxifen nonrecurrent cases) (Coffin, 1995; Ma et al., 2004).

The Predictor Analysis of Microarray 50 (PAM50, by Prosigna) is a 50-gene test that characterizes an individual tumor by intrinsic subtype (Parker et al., 2009). It was designed to determine the intrinsic subtype of a cancer using only 50 prespecified genes. Results from the PAM50 are used to generate the risk of recurrence (ROR) score, which can stratify patients with ER-positive disease into high, medium, and low subsets. The test can be performed on formalin-fixed, paraffin-embedded tissue with a high degree of analytical validity (Nielsen et al., 2010; Theodoros & Bergh, 2017).

Urokinase plasminogen activator (uPA) is a serine protease with an important role in cancer invasion and metastases (Stephens, Brunner, Janicke, & Schmitt, 1998). When bound to its receptor (uPAR), uPA converts plasminogen into plasmin and mediates degradation of the extracellular matrix during tumor cell invasion. High levels have been associated with shorter survival in women with breast cancer (Chappuis et al., 2001; Foekens et al., 2000; Malmstrom et al., 2001; Stephens et al., 1998). ASCO guidelines include the option for using uPA and PAI-1 to guide decisions on adjuvant systemic therapy for patients with node-negative, hormone-positive/HER2-negative disease, but not for patients with HER2-positive or triple-negative disease (Harris et al., 2016; Theodoros & Bergh, 2017). 

Test 

 Oncotype DX

MammaPrint  

EndoPredict  

Genomic Health  

Agendia  

Myriad  

breast cancer prognostic test  

breast cancer prognostic test  

breast cancer prognostic test  

Intended use

The test is intended for use in all newly diagnosed patients with early-stage (stage I, II or IIIa), breast cancer who have node-negative or node-positive (1-3), estrogen receptor-positive (ER+), HER2-negative disease to predict chemotherapy benefit

The test is indicated for breast cancer patients with: Breast Cancer Stage 1 or2; invasive carcinoma (infiltrating carcinoma); tumor size <5.0cm; lymph node negative; ER+ or ER-; HER2 neg or pos

The test is intended for use in patients with estrogen receptor-positive (ER+), human epidermal growth factor 2-negative (HER2-), early-stage breast cancer, node-negative or node-positive (1-3 positive nodes)

Score calculation

Gene expression results are used to generate a score that is a number between 0-100. A low score means the cancer has a lower chance of returning and patient has a lower chance of benefiting from chemotherapy. A high score means the cancer has a higher chance of returning and patient has a higher chance of benefiting from chemotherapy. For example, patients with a high score often choose more aggressive treatment options including chemotherapy, than patients with low scores.

Provides a numerical index with a range of -1 to +1, that is overlayed with a binary Low Risk / High Risk clinical classification system. The clinical classification threshold was set by the determination of the largest population of Low Risk patients that can safely withhold chemotherapy.

Combination of gene expression results score with the cancer’s size and nodal status to calculate an EPclin Score that categorizes the cancer as having either a high risk or low risk of distant recurrence.

Number of genes tested

21-gene signature

70-gene signature

12-gene signature

Technology

RT-PCR

microarray

RT-PCR

FDA status

Not FDA-approved

Approved in 2007

Not FDA-approved

Societies recognizing clinical utility

ASCO, EGAP, NCCN, NICE, ESMO

ASCO

ASCO

Regulatory Status
MammaPrint® was U.S. Food and Drug Association (FDA)-approved on February 6, 2007. MammaPrint® is performed in Agendia laboratories in the Netherlands and in California. MammaPrint is FDA cleared for use in women of all ages, with stage 1 or 2 breast cancer, invasive carcinoma, tumor size <5 cm, lymph node negative, estrogen receptor positive or negative, and HER2/neu positive or negative.

Prosigna™ received 510(k) clearance from

FDA based on substantial equivalence to MammaPrint® on September 6, 2013.

Other Breast Cancer Prognosis panels are considered laboratory developed tests (LDT); developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use. 

Policy:

  1. Use of the Oncotype DX 21-gene expression assay is considered MEDICALLY NECESSARY for the determination of the recurrence of risk for deciding whether or not to undergo adjuvant chemotherapy in women with primary, invasive breast cancer who meet all of the following criteria:
    • Node-negative (lymph nodes with micrometastases [less than two mm in size] are considered node negative for this policy statement) OR with 1-3 involved ipsilateral axillary lymph nodes when test results would impact treatment decisions
    • Hormone receptor positive (either estrogen-receptor [ER] or progesterone-receptor [PR] positive)
    • Human epidermal growth factor receptor two (HER2) negative
    • Tumor size > 0.5 cm
    • Histology is ductal, lobular, mixed or metaplastic 
    • Staging pT1, pT2, or pT3; and pN0 or pN1mi (≤ 2mm axillary node metastasis)
      • The 21-gene RT-PCR assay Oncotype DX should only be ordered on a tissue specimen obtained during surgical removal of the tumor and after subsequent pathology examination of the tumor has been completed and determined to meet the above criteria (i.e., the test should not be ordered on a preliminary core biopsy).
      • For patients who otherwise meet the above characteristics but who have multiple ipsilateral primary tumors, a specimen from the tumor with the most aggressive histological characteristics should be submitted for testing. It is not necessary to conduct testing on each tumor; treatment is based on the most aggressive lesion
  2. Use of EndoPredict or PAM50 (Prosigna), to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy is considered MEDICALLY NECESSARY in women with primary, invasive breast cancer with the same characteristics as considered medically necessary for Oncotype DX (1a – 1f; with one exception – the tests do not meet coverage criteria for individuals with 1-3 involved ipsilateral axillary lymph nodes)
  3. Use of Mammaprint to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy is considered MEDICALLY NECESSARY in women with high clinical risk per MINDACT categorization with primary, invasive breast cancer with the same characteristics as considered medically necessary for Oncotype DX (1a – 1f).
  4. Tumor testing for hormone receptor (Estrogen Receptor and Progesterone Receptor) expression and Human Epidermal Growth Factor Receptor 2 (HER2) overexpression is considered MEDICALLY NECESSARY for all women with newly diagnosed, non-metastatic breast cancer.
  5. Use of Mammaprint to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy is considered NOT MEDICALLY NECESSARY in women with low clinical risk per MINDACT categorization with primary, invasive breast cancer.
  6. In males, use of gene expression assays other than 21-gene RT-PCR-based assays are considered INVESTIGATIONAL.
  7. Use of other gene expression assays including, but not limited to, Mammostrat is INVESTIGATIONAL.  
  8. The use of Oncotype DX 21-gene expression for DCIS is considered INVESTIGATIONAL.

Rationale
American Society of Clinical Oncology (ASCO)
In 2007, the ASCO stated that, "In newly diagnosed patients with node-negative, estrogen-receptor positive breast cancer, the Oncotype DX assay can be used to predict the risk of recurrence in patients treated with tamoxifen. Oncotype DX may be used to identify patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy. In addition, patients with high recurrence scores appear to achieve relatively more benefit from adjuvant chemotherapy (specifically (C)MF) than from tamoxifen. There are insufficient data at present to comment on whether these conclusions generalize to hormonal therapies other than tamoxifen, or whether this assay applies to other chemotherapy regimens" (Harris et al, 2007).

ASCO also indicated that "the precise clinical utility and appropriate application for other multi-parameter assays, such as the MammaPrint assay, the so-called Rotterdam Signature, and the Breast Cancer Gene Expression Ratio are under investigation" (Harris et al, 2007).

In 2016, ASCO provided recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. ASCO recommends that "in addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer" (Harris, 2016).  

Regarding Oncotype DX, ASCO made the following recommendations:

  • If a patient has ER/PgR-positive, HER2-negative (node-negative) breast cancer, the clinician may use the 21-gene recurrence score to guide decisions on adjuvant systemic chemotherapy. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient has ER/PgR-positive, HER2-negative (node-positive) breast cancer, the clinician should not use the 21-gene RS to guide decisions on adjuvant systemic chemotherapy. Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate.
  •  If a patient has HER2-positive breast cancer or TN breast cancer, the clinician should not use the 21-gene RS to guide decisions on adjuvant systemic therapy. Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: strong.

In 2017 the ASCO (Krop et al., 2017), based on a review of the MINDACT study publication, revised their guidelines on Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer to state:

"Recommendation 1.1.1 (update of Recommendation 1.7).
If a patient has ER/PgR–positive, HER2-negative, node-negative, breast cancer, the MammaPrint assay may be used in those with high clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good prognosis population with potentially limited chemotherapy benefit (Type: evidence based; Evidence quality: high; Strength of recommendation: strong).  
Recommendation 1.1.2 (update of Recommendation 1.7).
If a patient has ER/PgR–positive, HER2-negative, node-negative, breast cancer, the MammaPrint assay should not be used in those with low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy as women in the low clinical risk category had excellent outcomes and did not appear to benefit from chemotherapy even with a genomic high-risk cancer (Type: evidence based; Evidence quality: high; Strength of recommendation: strong)." 

American Joint Committee on Cancer
The Expert Panel determined that :
"Multigene panels may provide prognostic and therapy predictive information that complements T, N, M and biomarker information. Use of these assays in not required for staging. The Breast Expert Panel included one multigene panel in Pathological Prognostic Staging, but others may be equally useful for clinical decision making."  

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group
In 2009, the EGAPP the found for Oncotype DX "adequate evidence from one higher quality study to support the association between RS and rates of 10-year distant metastasis, and adequate evidence to support the association between RS and chemotherapy benefit. Study subjects were mainly whites, and how characteristics of other demographic populations might affect test performance is not known" (EGAPP Working Group, 2009).  

With regard to MammaPrint, EGAPP found "that data were adequate to support an association between the MammaPrint Index and 5- or 10-year metastasis rates, but the relative efficacy of testing in ER-positive and -negative women is not clear. Study subjects were European, and how characteristics of other demographic populations might affect test performance is not known."

Also, with regard to the H:I test, EGAPP found that "the evidence available to assess clinical validity is inadequate, with a small number of studies in a variety of heterogeneous populations, and only one study that applies directly to the laboratory-developed test offered by Quest" (EGAPP Working Group, 2009).

The 2016 EGAPP Working Group guidelines state that there is "insufficient evidence to recommend for or against the use of Oncotype DX testing to guide chemotherapy treatment decisions in women with hormone receptor–positive, lymph node–negative, or lymph node–positive early breast cancer who are receiving endocrine therapy." The guidelines further state that "with regard to clinical utility, although there was evidence from prospective retrospective studies that the Oncotype DX test predicts benefit from chemotherapy, and there was adequate evidence that the use of Oncotype DX gene expression profiling in clinical practice changes treatment decisions regarding chemotherapy, no direct evidence was found that the use of Oncotype DX testing leads to improved clinical outcomes" (EGAPP Working Group, 2016).

National Comprehensive Cancer Network (NCCN)
The NCCN guidelines on Breast Cancer (NCCN, 2018) state that "the 21-gene RT-PCR assay recurrence score can be considered in select patients with 1-3 involved ipsilateral axillary lymph nodes to guide the addition of combination chemotherapy to standard hormone therapy".

The NCCN recommends the use of the 21-gene reverse transcriptase polymerase chain reaction (RT-PCR) assay for determining the use of adjuvant chemotherapy in patients with the following tumor characteristics:

  • Hormone receptor-positive;
  • HER2 [human epidermal growth factor receptor 2]-negative;
  • Ductal, lobular, mixed or metaplastic histology;
  • pT1, pT2 or pT3 stage; and pN0 or pN1mi (≤ 2mm axillary node metastasis);
  • Tumor >0.5 cm.

In regard to other multigene assays, the NCCN guidelines state: "other prognostic multigene assays may be considered to help asses risk of recurrence but have not been validated to predict response to chemotherapy"

"The NCCN Panel members acknowledge that many assays have been clinically validated for prediction of prognosis. However, based on the currently available data, the panel believes that the 21-gene assay has been best validated for its use as a prognostic test as well as in predicting who is most likely to respond to systemic chemotherapy".

The National Institute for Health and Care Excellence (NICE) recommends Oncotype DX "as an option for guiding adjuvant chemotherapy decisions for people with estrogen receptor positive (ER+), lymph node negative (LN−) and human epidermal growth factor receptor 2 negative (HER2−) early breast cancer if the person is assessed as being at intermediate risk and information on the biological features of the cancer provided by Oncotype DX is likely to help in predicting the course of the disease and would therefore help when making the decision about prescribing chemotherapy" (NICE, 2013).

NICE also indicates that "MammaPrint, IHC4 and Mammostrat are only recommended for use in research in people with ER+, LN− and HER2− early breast cancer, to collect evidence about potentially important clinical outcomes and to determine the ability of the tests to predict the benefit of chemotherapy. The tests are not recommended for general use in these people because of uncertainty about their overall clinical benefit and consequently their cost effectiveness" (NICE, 2013).

References:

  1. Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K. K., Carter, S. L., Frederick, A. M., . . . Meyerson, M. (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature, 486(7403), 405-409. doi:10.1038/nature11154
  2. CGAN. (2012). Comprehensive molecular portraits of human breast tumours. Nature, 490(7418), 61-70. doi:10.1038/nature11412
  3. Chappuis, P. O., Dieterich, B., Sciretta, V., Lohse, C., Bonnefoi, H., Remadi, S., & Sappino, A. P. (2001). Functional evaluation of plasmin formation in primary breast cancer. J Clin Oncol, 19(10), 2731-2738. doi:10.1200/jco.2001.19.10.2731
  4. Coffin, J. M. (1995). HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science, 267(5197), 483-489.
  5. Curtis, C., Shah, S. P., Chin, S. F., Turashvili, G., Rueda, O. M., Dunning, M. J., . . . Aparicio, S. (2012). The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature, 486(7403), 346-352. doi:10.1038/nature10983
  6. Darby, S., McGale, P., Correa, C., Taylor, C., Arriagada, R., Clarke, M., . . . Peto, R. (2011). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet, 378(9804), 1707-1716. doi:10.1016/s0140-6736(11)61629-2
  7. Davies, C., Godwin, J., Gray, R., Clarke, M., Cutter, D., Darby, S., . . . Peto, R. (2011). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet, 378(9793), 771-784. doi:10.1016/s0140-6736(11)60993-8
  8. Ding, L., Ellis, M. J., Li, S., Larson, D. E., Chen, K., Wallis, J. W., . . . Mardis, E. R. (2010). Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature, 464(7291), 999-1005. doi:10.1038/nature08989
  9. Dubsky, P., Brase, J. C., Jakesz, R., Rudas, M., Singer, C. F., Greil, R., . . . Filipits, M. (2013). The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer, 109(12), 2959-2964. doi:10.1038/bjc.2013.671
  10. Ellis, M. J., Ding, L., Shen, D., Luo, J., Suman, V. J., Wallis, J. W., . . . Mardis, E. R. (2012). Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature, 486(7403), 353-360. doi:10.1038/nature11143
  11. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2016). Recommendations from the EGAPP Working Group: does the use of Oncotype DX tumor gene expression profiling to guide treatment decisions improve outcomes in patients with breast cancer? Genetics in Medicine, 18: 770-779.
  12. Foekens, J. A., Peters, H. A., Look, M. P., Portengen, H., Schmitt, M., Kramer, M. D., . . . Klijn, J. G. (2000). The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res, 60(3), 636-643.
  13. Forouzanfar, M. H., Foreman, K. J., Delossantos, A. M., Lozano, R., Lopez, A. D., Murray, C. J., & Naghavi, M. (2011). Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet, 378(9801), 1461-1484. doi:10.1016/s0140-6736(11)61351-2
  14. Harris, L. N., Ismaila, N., McShane, L. M., Andre, F., Collyar, D. E., Gonzalez-Angulo, A. M., . . . Hayes, D. F. (2016). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 34(10), 1134-1150. doi:10.1200/jco.2015.65.2289
  15. Harris, L.N., Fritsche, H., Mennel, R., … Bast, R.C. (2007). American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. Journal of Clinical Oncology, 25(33): 5287-5312.
  16. Krop, I., Ismaila, N., Andre, F., Bast, R. C., Barlow, W., Collyar, D. E., . . . Stearns, V. (2017). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol, Jco2017740472. doi:10.1200/jco.2017.74.0472 
  17. Ma, X. J., Wang, Z., Ryan, P. D., Isakoff, S. J., Barmettler, A., Fuller, A., . . . Sgroi, D. C. (2004). A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell, 5(6), 607-616. doi:10.1016/j.ccr.2004.05.015 
  18. Malmstrom, P., Bendahl, P. O., Boiesen, P., Brunner, N., Idvall, I., & Ferno, M. (2001). S-phase fraction and urokinase plasminogen activator are better markers for distant recurrences than Nottingham Prognostic Index and histologic grade in a prospective study of premenopausal lymph node-negative breast cancer. J Clin Oncol, 19(7), 2010-2019. doi:10.1200/jco.2001.19.7.2010 
  19. Mamounas, E. P., Tang, G., Fisher, B., Paik, S., Shak, S., Costantino, J. P., . . . Wolmark, N. (2010). Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol, 28(10), 1677-1683. doi:10.1200/jco.2009.23.7610 
  20. NCCN. (2018). NCCN Clinical Practice Guidelines in Oncology; Breast Cancer v1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx 
  21. National Comprehensive Cancer Network (2016). NCCN Practice Guidelines in Oncology: Breast Cancer, Version 2.2016. Retrieved on March 10, 2017 from https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
  22. National Comprehensive Cancer Network (2014). NCCN Practice Guidelines in Oncology: Breast Cancer, Version 2.2014. Retrieved March, 2014 from www.nccn.org.
  23. National Institute for Health and Care Excellence (2013). Gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat. Diagnostics Guidance (DG10). Issued: September 2013. Retrieved online at: www.nice.org.uk/dg10
  24. Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K. K., Carter, S. L., Frederick, A. M., . . . Meyerson, M. (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature, 486(7403), 405-409. doi:10.1038/nature11154
  25. CGAN. (2012). Comprehensive molecular portraits of human breast tumours. Nature, 490(7418), 61-70. doi:10.1038/nature11412
  26. Chappuis, P. O., Dieterich, B., Sciretta, V., Lohse, C., Bonnefoi, H., Remadi, S., & Sappino, A. P. (2001). Functional evaluation of plasmin formation in primary breast cancer. J Clin Oncol, 19(10), 2731-2738. doi:10.1200/jco.2001.19.10.2731
  27. Coffin, J. M. (1995). HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science, 267(5197), 483-489.
  28. Curtis, C., Shah, S. P., Chin, S. F., Turashvili, G., Rueda, O. M., Dunning, M. J., . . . Aparicio, S. (2012). The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature, 486(7403), 346-352. doi:10.1038/nature10983
  29. Darby, S., McGale, P., Correa, C., Taylor, C., Arriagada, R., Clarke, M., . . . Peto, R. (2011). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet, 378(9804), 1707-1716. doi:10.1016/s0140-6736(11)61629-2
  30. Davies, C., Godwin, J., Gray, R., Clarke, M., Cutter, D., Darby, S., . . . Peto, R. (2011). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet, 378(9793), 771-784. doi:10.1016/s0140-6736(11)60993-8
  31. Ding, L., Ellis, M. J., Li, S., Larson, D. E., Chen, K., Wallis, J. W., . . . Mardis, E. R. (2010). Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature, 464(7291), 999-1005. doi:10.1038/nature08989
  32. Dubsky, P., Brase, J. C., Jakesz, R., Rudas, M., Singer, C. F., Greil, R., . . . Filipits, M. (2013). The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer, 109(12), 2959-2964. doi:10.1038/bjc.2013.671
  33. Ellis, M. J., Ding, L., Shen, D., Luo, J., Suman, V. J., Wallis, J. W., . . . Mardis, E. R. (2012). Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature, 486(7403), 353-360. doi:10.1038/nature11143
  34. Foekens, J. A., Peters, H. A., Look, M. P., Portengen, H., Schmitt, M., Kramer, M. D., . . . Klijn, J. G. (2000). The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res, 60(3), 636-643.
  35. Forouzanfar, M. H., Foreman, K. J., Delossantos, A. M., Lozano, R., Lopez, A. D., Murray, C. J., & Naghavi, M. (2011). Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet, 378(9801), 1461-1484. doi:10.1016/s0140-6736(11)61351-2
  36. Harris, L. N., Ismaila, N., McShane, L. M., Andre, F., Collyar, D. E., Gonzalez-Angulo, A. M., . . . Hayes, D. F. (2016). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 34(10), 1134-1150. doi:10.1200/jco.2015.65.2289
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Coding Section

 Code

Number 

Description 

CPT  

81479

Unlisted molecular pathology procedure

 

81518 (effective 01/01/2019)

Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 11 genes (7 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithms reported as percentage risk for metastatic recurrence and likelihood of benefit from extended endocrine therapy 

 

81519

Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score

 

81520

Oncology (breast), mRNA gene expression profiling by hybrid capture of 58 genes (50 content and 8 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence risk score

 

81521

Oncology (breast), mRNA, microarray gene expression profiling of 70 content genes and 465 housekeeping genes, utilizing fresh frozen or formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk of distant metastasis

 

81599

Unlisted multianalyte assay with algorithmic analysis-EndoPredict

 

84999

Unlisted chemistry 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 

 

88367 

Morphometric analysis, in situ hybridization (quantitative or semi-quantitative), using computer-assisted technology, per specimen; each multiplex probe stain procedure 

 

88368 

Morphometric analysis, in situ hybridization (quantitative or semi-quantitative), manual, per specimen; initial single probe stain procedure 

 

88381 

Microdissection (ie, sample preparation of microscopically identified target); manual 

 

S3854 

Gene expression profiling panel for use in the management of breast cancer treatment 

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     

07/12/2019 

Annual review, updating coding and policy. Policy updates are in line with NCCN recommendations and relate to tumor site and type, potential treatment, staging and timing of diagnosis. Updating verbiage related to testing for males for clarity.  

12/21/2018 

Updating with 2019 codes.  

07/24/2018 

Annual review, reformatting entire policy. Expanding medical necessity criteria to allow Mammaprint testing for some indications. 

12/7/2017 

Updating policy with 2018 coding. No other changes. 

07/19/2017 

Annual review, updating policy criteria related to DX 21 gene expression, otherwise, no change to policy intent. 

04/25/2017 

Updated category to Laboratory. No other changes 

12/06/2016 

Interim review, adding medical necessity for Prosigna and EndoPredict testing. Updating background, description, guidelines, regulatory status, rationale and references. 

02/01/2016 

 Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references.

02/16/2015 

Interim review, added additional criteria for medical necessity regarding the histology of the tumor, added additional investigational tests, added that gene expression profiling as a technique of managing the treatment of ductal cardinoma in situ is investigational and that repeat gene expression profiling is investigational.  

01/28/2015 

Annual review, the following added to policy:The use of other gene expression assays, MammaPrint® 70-gene signature, Mammostrat® Breast Cancer Test, the Breast Cancer Index SM, BreastOncPx, NexCourse® Breast IHC4, Prosigna BreastPRS, and EndoPredict for any indication is considered investigational.

01/30/2014

Annual Review

 


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