This document addresses the use of genetic profiling of breast tumors as a technique of predicting breast cancer recurrence and response to therapy.

Medically Necessary: 

Gene expression profiling with the Oncotype™ DX breast cancer assay as a technique of managing the treatment of breast cancer is considered medically necessary when all of the following criteria are met:

1. Individual has had surgery and full pathological evaluation of the specimen has been completed; and
2. Histology:
   • Ductal; or
   • Lobular: or
   • Mixed; or
   • Metaplastic; and
   • NOT tubular or colloid and
3. Estrogen receptor positive (ER+), or progesterone receptor positive (PR+), or both; and
4. HER2 receptor negative; and
5. pN0 (node negative) or pN1mi with axillary lymph node micrometastasis less than or equal to 2mm; and:
6. Any of the following:
   1. Tumor size 0.6-1.0 cm moderate/poorly differentiated; or
   2. Tumor size 0.6-1.0 cm and well-differentiated with any of the following unfavorable features: angiolymphatic invasion, or high nuclear grade, or high histologic grade; or
   3. Tumor greater than 1.0 cm and less than or equal to 4.0 cm; and
7. Not a pT4 lesion; and
8. Chemotherapy is a therapeutic option being considered and will be supervised by the practitioner ordering the gene expression profile.

NOTE 1: "Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy.  The benefits of chemotherapy and of endocrine therapy are additive.  However, the absolute benefit from chemotherapy may be small.  The decision to add chemotherapy to endocrine therapy should be individualized, especially in those with a favorable prognosis and in women greater than or equal to 60y where the incremental benefit of chemotherapy may be smaller.

Available data suggest sequential or concurrent endocrine therapy with radiation therapy is acceptable." ^A
NOTE 2: "There are insufficient data to make chemotherapy recommendations for those over 70y old.  Treatment should be individualized with consideration of comorbid conditions."^A

^A National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (V.1.2010). October 23, 2009. Page BINV-6. For additional information:  http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.  Accessed on March 29, 2011.

Not Medically Necessary:

Gene expression profiling with the Oncotype™ DX breast cancer assay as a technique of managing the treatment of breast cancer is considered not medically necessary when the criteria above have not been met.

Investigational and Not Medically Necessary: 

Gene expression profiling as a technique of managing the treatment of breast cancer is considered investigational and not medically necessary when a gene profiling test other than the Oncotype™ DX breast cancer assay is being used, including but not limited to:

1. Breast Cancer Gene Expression Ratio (also know as Theros H/I^SM)
2. Insight^® DX Breast Cancer Profile
3. MammaPrint^®  (also referred to as the "Amsterdam signature")
4. The 76-gene "Rotterdam signature" assay
5. The 41-gene signature assay.
6. Mammostrat
7. THEROS Breast Cancer Index^SM

The selection of individuals with breast cancer who may be candidates for chemotherapy is a complex and inexact science at this time.  The current tools available for recurrence risk assessment are limited and do not allow for great accuracy in the selection of appropriate individuals who would and would not benefit from treatment with chemotherapeutic agents.  More precise identification of these individuals could improve health outcomes through more appropriate chemotherapy use, mitigation of unnecessary treatment, and decreased adverse chemotherapy-related events.

The use of gene expression profiling assays has been proposed as a tool for identification of chemotherapy-appropriate individuals.  There are currently several different gene expression profiling assays, in various stages of development, that are intended for eventual use in identifying those individuals at low risk of recurrence for whom adjuvant chemotherapy can be avoided.  These are the 21-gene Oncotype™ DX (Genomic Health, Inc., Redwood City, CA), the 70-gene MammaPrint^® (Agendia, BV, Amsterdam, Holland; also referred to as the "Amsterdam signature"), the 76-gene "Rotterdam signature" (Veridex, LLC, Warren, NJ), and a 41-gene signature reported by Ahr (2001). Another test, the Breast Cancer Gene Expression Ratio (also known as Theros H/I^SM_, by bioTheranostics, San Diego, CA and marketed by LabCorp) is a test that measures the expression of 2 separate genes that have an association with breast cancer recurrence (the homeobox gene [HOXB13] and interleukin-17B receptor gene [IL-17BR]).  It has been proposed that expression ratio of these two genes may assist in predicting disease recurrence.  Finally, the Mammostrat^® test (Applied Genomics, Huntsville, AL) is a biomarker test that measures the expression of substances that have been associated with breast cancer. 

Oncotype DX was developed using the candidate gene method: a relatively small number of genes known to be involved in breast cancer progression were selected and by analyzing expression of these genes in tumor specimens, a 21-gene signature predicting recurrence was developed.  The other 3 assays were developed by analyzing gene expression of tumor specimens on large scale microarrays with thousands of gene transcripts, followed by pattern or cluster analysis to identify a much smaller gene signature that correlated with disease recurrence.  Of these three, two have been compared: a 70-gene panel (MammaPrint^® or "Amsterdam signature") and a 76-gene panel ("Rotterdam signature") overlap by only 3 genes, due at least partly to the use of different microarray platforms in developing the panels.  More recent studies indicate that the 2 panels share 21 biological pathways, if not the same genes.

All these panels were developed using banked specimens from clinical trials or cohorts for which long-term outcomes were already known.  This is an efficient method for defining and establishing the clinical validity of the gene expression signatures.  Clinical validity for this application is defined as evidence supporting the ability of the panel to accurately predict outcomes such as disease recurrence, disease-free survival, or overall survival.  Evidence of clinical validity has been reported in full-length journal publications for 3 panels, Oncotype DX, MammaPrint and the Breast Cancer Gene Expression Ratio. 

At this time no prospective trials have been conducted in which any of these assays are prospectively used to select women with early stage breast cancer for adjuvant chemotherapy.  The National Cancer Institute's Program for the Assessment of Clinical Cancer Tests (PACCT) has proposed a prospective trial in which node-negative, estrogen receptor (ER)-positive individuals with breast cancer would be assigned hormone therapy only based on a low Recurrence Score (RS) derived from the Oncotype DX assay. 

Despite the lack of prospective studies, several retrospective studies have been published that support the clinical utility of Oncotype DX.  One in particular was reported in 2006 in the Journal of Clinical Oncology (Paik, 2006).  Available banked specimens from the randomized tamoxifen + chemotherapy-treated arms of NSABP trial B-20 were compared to the tamoxifen-only arm (samples also used as the test set to develop the assay) and gene expression signatures were correlated to chemotherapy benefit.  The 424 selected subjects with high RS (≥31) had an absolute increase in distant recurrence free survival (DRFS) at 10 years of 27.6 + 8% (mean ± SE; p=0.01) compared to the tamoxifen-only group.  Subjects with low RS (<18) had little benefit from chemotherapy (absolute DRFS increase at 10 years, -1.1 ± 2.2%).  Interaction between chemotherapy and RS was significant at p<0.05.  These results suggest that the Oncotype DX RS is closely associated with the magnitude of the benefit from chemotherapy.

A second study by Habel and colleagues published in 2006 described a retrospective case-control study of 4,964 subjects with node negative invasive breast cancer.  In this study cases (n=220) were defined as subjects who died of breast cancer and controls (n=570) were described as individually matched breast cancer subjects who were alive at the time of the study.  The results of the study found that the RS from Oncotype DX assay was associated with the risk of breast cancer-related death in estrogen receptor (ER)-positive, tamoxifen treated subjects.  At 10 years, the risk for death in this population was found to be 2.8% in low RS individuals, 10.7% in intermediate RS individuals and 15.5% in high RS individuals.  Individuals who were ER-positive but not treated with tamoxifen had a risk of death of 6.2% in low RS individuals, 17.8% in intermediate RS individuals and 19.9% in high RS individuals.

At this time the available evidence addressing the use of the Oncotype DX gene expression profiling test for breast cancer does not provide definitive data to decisively guide the use of this test in clinical practice.  The National Comprehensive Cancer Network (NCCN) Practice Guidelines in Oncology: Breast Cancer (V2.2008) provides a framework in which this test may be used.  The recommendations made in the NCCN Practice Guideline regarding the Oncotype DX test are based upon a Category of Evidence and Consensus 2B, which is defined as follows; "There is nonuniform consensus (but no major disagreement) based upon lower-level evidence including clinical experience , that the recommendation is appropriate."  This categorization is indicative of the uncertainty within the clinical practice community regarding specific aspects of the available data and its interpretation. 

In January 2008 the Agency for Healthcare Research and Quality (AHRQ) released a technology assessment of the Oncotype DX test and other similar gene profiling tests for breast cancer.  The Assessment concludes, "There are still uncertainties about the optimal use of this test in practice. First, while the cutoffs are valuable for test validation purposes, it is not clear whether the current thresholds actually correspond to the cutoffs that would be derived using a formal decision-analytic approach based on utility assessments….The second uncertainty is the optimal use of conventional predictors. While the RS has been shown to have more value than most predictors, the same studies show that clinical predictors retain predictive value, and clinical prediction models continue to evolve and improve."

Review of the literature indicates that data addressing the use of the Oncotype DX test for tumors greater than 4.0 cm is sparse.  In the major trials available to date, including the NSABP B-14 and B-20 studies used in development of the Oncotype DX algorithm as reported, more than 95% of all participants had tumors less than or equal to 4.0 cm (Fisher, 1994; Fisher, 1997; Habel, 2006; Paik 2004; Paik 2006).

Regarding the MammaPrint™ test, the translational research network of the Breast International Group (TRANS-BIG) is planning a randomized clinical trial to determine therapy for node-negative individuals with breast cancer.  In the Microarray for Node Negative Disease may Avoid Chemotherapy Trial (MINDACT), 5000 subjects will be randomly assigned to treatment based on conventional histopathological and clinical criteria for recurrence or based on the MammaPrint 70-gene expression profile.  Currently the only published data from this group are two validation studies (Buyse, 2006; Desmet 2007.)  Several additional studies have been published addressing the MammaPrint assay.  Mook and colleagues describe a pair of trials evaluating the prognostic ability of the MammaPrint.  The first study involved retrospective data and tumor samples from 241 subjects with node positive breast cancer (Mook, 2009).  The 10-year distant metastases free survival (DMFS) and breast cancer-specific survival (BCSS) probabilities were reported to be 91% and 96% respectively for the "good prognosis" group and 76% for both DMFS and BCSS for the "poor prognosis" group.  These results were compared to those obtained using Adjuvant! Online and judged to be superior in predictive value.  The second study involved tumor samples and retrospective clinical data from 184 subjects between the age of 55 and 70 previously treated from breast cancer (Mook, 2010).  The authors report that the BCSS at 5 years was 99% for the good-prognosis signature versus 80% for the poor-prognosis signature group (P = 0.036).  They concluded that MammaPrint results were a significant and independent predictor of BCCS during the first 5 years of follow-up.  The other two studies evaluated the use of the MammaPrint test in subjects with node-negative disease (Bueno-de-Mesquita, 2007; Bueno-de-Mesquita, 2009).  In both of these studies MammaPrint prognostic index results were compared to other commonly used clinicopathologic risk indexes, and both reported favorable results.  None of these studies has evaluated the impact of the MammaPrint test on overall survival, nor on the avoidance of unnecessary treatment with chemotherapy.  Finally, Knauer and others reported the results of a quasi meta-analysis study involving the data from previous studies.  The data set included data from 541 subjects who had received either breast conserving surgery or mastectomy with sentinel node biopsy or axillary lymph node dissection followed by radiotherapy.  For this study, data for all subjects who received endocrine therapy (ET) alone or ET plus adjuvant chemotherapy (ET+CT) was reanalyzed for benefit of adjuvant CT using groups classified as good or poor prognosis based upon MammaPrint testing as a framework.  Additionally, time-to-event data was gathered and analyzed from the pooled data.  The authors reported that BCSS and distant disease-free survival (DDFS)  were significantly better in subjects classified as having a good prognosis compared to those classified as poor prognosis (p < 0.01).  Furthermore, the data showed that subjects in the poor prognosis group who had received ET+CT had a significantly longer BCSS and DDFS when compared to those in the good prognosis group (BCSS 94% vs. 81%, p < 0.01; DDFS 88% vs. 76%, p < 0.01).  No differences between the ET and EC+CT groups were found in relation to the benefit of CT in the good prognosis group.

Further data is needed to demonstrate  the potential benefits of MammaPrint testing on health outcomes in women with breast cancer. 

The current available data addressing the Breast Cancer Gene Expression Ratio test is limited to one retrospective study (Goetz; 2006.)  In this study, tumor blocks from 206 women with breast cancer were examined for HOXB13/IL-17BR expression ratio (H:I ratio).  They found that in lymph node positive subjects (n=86) the H:I ratio was not associated with relapse or survival.  However, in node negative subjects (n=103) a high H:I ratio was associated with significantly worse disease free survival, relapse free survival, and overall survival.  Again, while the results of this study are promising, they are insufficient to allow generalized conclusions on how this test would perform in other populations.

Evidence addressing the use of the Rotterdam 76-gene assay, as well as the 41-gene assay, is also limited by insufficient data.  Further data regarding these tests is required to properly assess their clinical utility.

A study published by Linke and colleagues in 2006 describes a retrospective case series study of 324 subjects with breast cancer.  This study used an early version of the Insight DX Breast Cancer Profile test.  The results of this test showed promise in being able to predict outcomes in tamoxifen treated individuals with breast cancer.  However, this is the only peer-reviewed published study addressing this test, and thus there has been no independent confirmation that this test prospectively results in incrementally improved care and outcomes.

At this time the data available do not support the use of the MammaPrint, Breast Cancer Gene Expression Ratio test (H:I Ratio), the Rotterdam 76-gene assay, or the Insight DX Breast Cancer Profile.  These tests are not currently recommended by the NCCN guidelines.  Additionally, two other authoritative bodies have provided statements regarding the use of these tests.  The American Society of Clinical Oncology (ASCO)

Recommendations for the Use of Tumor Markers in Breast Cancer (Harris, 2007) indicate that these tests are not yet ready for clinical use.  Their recommendations state; "The precise clinical utility and appropriate application for other multiparameter assays, such as the MammaPrint assay, the "Rotterdam Signature," and the Breast Cancer Gene Expression Ratio are under investigation."  Also, AHRQ technology assessment from January 2008 states; "The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies."

Several abstracts and posters have been presented at various meetings addressing the diagnostic validity and clinical validity of the Mammostrat test.  One published study by Ring and others (2006) discusses a single validation study for this test, but no data has been made available regarding the impact of this test on clinical outcomes.  Further studies seeking evidence addressing the clinical utility of this test are warranted.

The THEROS Breast Cancer Index has been marketed for predictive risk assessment as well.  At this time there are no peer-reviewed published studies describing this test or its possible impact on clinical outcomes.

In March 2008 Marchionni and colleagues published a systematic review of the data addressing the use of gene expression profiling tests in breast cancer.  In that document the authors conclude, "Although these tests show great promise to improve predictions of prognosis and treatment benefit for women with early stage breast cancer, more must be learned about the extent of that improvement, in whom it is most improved, and how the tests are best incorporated into decision making about current breast cancer treatment."

Hatzis and colleagues published a paper in 2011 describing the development of a genomic predictor of response and survival in subjects with invasive breast cancer undergoing treatment with taxane-anthracycline chemotherapy.  The predictive test was applied to a discovery cohort of 310 samples and then evaluated in an independent validation cohort of 198 subjects who received sequential taxane and anthracycline chemotherapy. Subjects in the validation cohort who were predicted to be treatment sensitive had 56% probability of excellent pathologic response and DRFS of 92%, with an absolute risk reduction (ARR) of 18%.  Survival was predicted in ER-positive and ER-negative subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for subjects predicted to be responsive to chemotherapy. The authors stated that their genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified individuals with high probability of survival following taxane and anthracycline chemotherapy.  It must be noted the predictor described is not commercially available.  Additionally, this study only attempts to support a connection between genomic test results and a clinical outcome, but does not show that making treatment decisions based on such results, prospectively, improves outcome.

Clinical evidence has demonstrated that among individuals with breast cancer there is a continuum of disease recurrence risk, based on many factors including age, the presence of various hormone receptors in tumor samples, tumor size, whether or not the cancer has spread outside the breast, and others.  Clinicians have, for practical use, divided this continuum up into three risk categories: 1) low risk, 2) intermediate risk, and 3) high risk.  These risk categories have been used as a method of helping to determine what treatment methods to use for specific individuals.  In individuals deemed at high risk for disease recurrence, the medical evidence has shown that the use of chemotherapy in addition to other treatment may provide a significant survival benefit.  In low risk individuals, the data has shown that chemotherapy in addition to other treatment does not provide any significant benefits.  However, the available information regarding whether or not intermediate risk individuals benefit from chemotherapy is unclear.  Traditionally, treating clinicians have to balance each individual's risk of disease recurrence with the risks of chemotherapy, which include hair loss, nausea, vomiting, weakness, infection, and others.  

Recently a new type of test, the gene expression profiling assay, has been developed to help clinicians determine which populations of intermediate risk individuals would benefit from chemotherapy.  Gene expression profiling assays measure the presence of a variety of genes which have been associated with the recurrence of breast cancer.  Using these tests, in conjunction with other traditional risk assessment methods, clinicians may be able to more accurately determine which intermediate risk individuals would benefit from chemotherapy, and which individuals would not.  In this way individuals most likely to benefit from chemotherapy are identified and receive needed care, and those individuals who would not benefit are spared the unnecessary treatment and risks associated with chemotherapy without adversely affecting disease-free and overall survival outcomes.

Estrogen receptor status: A laboratory finding related to the presence or absence of cellular receptors for the hormone estrogen. 

HER2 receptor status: A laboratory finding related to the presence or absence of cellular receptors for HER2/neu (also known as ErbB-2, ERBB2) protein family.  HER2 is notable for its role in the pathogenesis of breast cancer and as a target of treatment.  There are two different methods by which HER2 receptor status can be discovered;  the first is immunohistochemistry (IHC) and the other is fluorescence in situ hybridization (FISH).  According to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) recommendations for HER2 testing for breast cancer (Wolff, 2007), scoring of these tests is as follows:

• For IHC testing (ranges from 0 to 3+):
  • Zero is HER2 negative
  • 1+ is considered HER2 negative
  • 2+ is considered a borderline or equivocal result
  • 3+ is HER2 positive
• For FISH testing, results are expressed in the ratio of HER2 gene/chromosome 17 or in the numbers of HER2 gene copies present in the sample: 
  • FISH ratio of less than 1.8 or HER2 gene copy of less than 4 is negative
  • FISH ratio 1.8 to 2.2 or HER2 gene copy of between 4 to 6 is borderline or equivocal
  • FISH ratio greater than 2.2 or HER2 gene copy of greater than 6 is positive

Note 1: FISH testing is recommended in individuals with an equivocal (2+) expression by IHC.
Note 2: "Borderline FISH Samples (eg, an average HER2gene/chromosome 17 ratio of 1.8-2.2 or an average HER2gene copy number >4 - <6) should undergo: counting of additional cells; retesting by FISH; or reflex testing by validated IHC method which is at least 95% concordant with FISH as described above" (NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (V.2.2011) page BINV-A, footnote 5).

Histology: A method of categorizing tissues by evaluating cells and tissues at the cellular level with microscopic examination; the following are several histological categories of breast cancer:

• Colloid
• Ductal
• Lobular
• Metaplastic
• Mixed
• Tubular.

Progesterone receptor status: A laboratory finding related to the presence or absence of cellular receptors for the hormone progesterone. 

TNM (tumor size, nodal involvement, and metastasis) classification: A classification system used for characterizing the size and location of breast cancer. The system is described below:
(Note: A prefix of "p" indicates by pathology report)

Primary Tumor:

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

When services may be Medically Necessary when criteria are met: 

When services are Not Medically Necessary:
For the procedure code listed above specified as Oncotype™ DX test, when criteria are not met for the diagnoses listed.

When services are Investigational and Not Medically Necessary:
For the procedure code listed above when specified as any other type of gene expression testing for breast cancer, for all other diagnoses, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Ahr A, Holtrich U, Solbach C, et al Molecular classification of breast cancer patients by gene expression profiling.  J Pathol. 2001; 195(3):312-320.
2. Ahr A, Karn T, Solbach C, et al.  Identification of high risk breast-cancer patients by gene expression profiling.  Lancet. 2002; 359(9301):131-132.
3. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet. 2010; 11(1):55-65.
4. Ayers M, Symmans WF, Stec J, et al.  Gene expression profiles predict complete pathological response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer.  J Clin Oncol. 2004; 22(12):2284-2293.
5. Borie N, Bertucci F, Groulet-Martinec A, et al. Gene expression profiling defines new molecular classes and predicts prognosis in breast cancer patients treated with adjuvant chemotherapy: development of a clinical tool to improve management of breast cancer.  Breast Cancer Res Treat. 2004; 88(Suppl ):A5035.
6. Borie N, Birnbaum D, Bertucci F, et al. Breast cancer Profilechip: Utilization of microarray technology to predict prognosis and improve clinical management of breast cancer.  J Clin Oncol. 2004; 22(14 Suppl):9658.
7. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognosis signature in node-negative breast cancer. Breast Cancer Res Treat. 2009; 117(3):483-495.
8. Bueno-de-Mesquita JM, van Harten WH, Retel VP, et al. Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol. 2007; 8(12):1079-1087.
9. Buyse M, Loi S, van't Veer L, et al.; TRANSBIG Consortium. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006; 98(17):1183-1192.
10. Chang JC, Wooten EC, Tsimelzon A, et al.  Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer.  Lancet. 2003; 362(9381):362-369.
11. Chang JC, Makris A, Gutierrez MC, et al. Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients. Breast Cancer Res Treat. 2008; 108(2):233-240.
12. Cobleigh MA, Bitterman P, Baker J, et al.  Tumor gene expression predicts distant disease-free survival (DDFS) in breast cancer patients with 10 or more positive nodes:  high throughput RT-PCR assay of paraffin-embedded tumor tissues.  Prog Proc Am Soc Clin Oncol. 2003; 22:850.
13. Cobleigh MA, Tabesh B, Bitterman P, et al. Tumor gene expression and prognosis in breast cancer patients with 10 or more positive nodes.  Clin Cancer Res. 2005; 11(24 Pt 1):8623-8631.
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19. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997; 89(22):1673-1682.
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25. Hannemann J, Oosterkamp HM, Bosch CA, et al.  Changes in gene expression profiling due to primary chemotherapy in patients with locally advanced breast cancer.  J Clin Oncol. 2004; 22 (14 Suppl):502.
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38. Paik S, Shak S, Tang G, et al.  Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients—NSABP studies B-20 and B-14.  Breast Cancer Res Treat. 2003; 82:A16.
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40. Paik S, Shak S, Tang G, et al.  Risk classification of breast cancer patients by the Recurrence Score assay: comparison to guidelines based on patient age, tumor size, and tumor grade.  Breast Cancer Res Treat. 2004; 88(Suppl 1):A104.
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43. Piccart MJ, Loi S, Van't Veer L, et al.  Multi-center external validation study of the Amsterdam 70-gene prognostic signature in node negative untreated breast cancer: are the results still outperforming the clinical-pathological criteria?  Breast Cancer Res Treat .2004; 88(Suppl 1):A38.
44. Rayhanabad JA, Difronzo LA, Haigh PI, Romero L. Changing paradigms in breast cancer management: introducing molecular genetics into the treatment algorithm. Am Surg. 2008; 74(10):887-890.
45. Ring BZ, Seitz RS, Beck R, et al. Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer. J Clin Oncol. 2006; 24(19): 3039-3047.
46. van de Vijver MJ, He YD, van't Veer LJ, et al.  A gene-expression signature as a predictor of survival in breast cancer.  N Engl J Med. 2002; 347(25):1999-2009.
47. van't Veer LJ, Dai H, He Y, et al.  Gene expression profiles predicting outcome of disease are different for young and older age breast cancer patients.  Breast Cancer Res Treat. 2004; 88(Suppl 1):A102.
48. van't Veer MJ, He YD, Van't veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002; 347(25):1999-2009.
49. van 't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415(6871):530-536.
50. Wang Y, Klijn J, Zhang Y, et al.  Pathway analysis and validation of the 76-gene prognostic signature in lymph node negative (LNN) primary breast cancer.  Breast Cancer Res Treat. 2004; 88(Suppl 1):A103.
51. Wittner BS, Sgroi DC, Ryan PD, et al. Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort. Clin Cancer Res. 2008; 14(10):2988-2993.
52. Wolff A, Hammond MEH, Schwartz JN, et al. 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; 25(1):118-145.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment Number 160: Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes. January 2008. Available at: http://www.ahrq.gov/clinic/tp/brcgenetp.htm. Accessed on March 10, 2011.
2. Blue Cross Blue Shield Association. Gene Expression Profiling for Managing Breast Cancer Treatment. TEC Assessment, 2005; 20(3).
3. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.  Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer? Genet Med. 2009; 11(1):66-73.
4. Harris L, Fritsche H, Mennel R, et al.  American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer.  J Clin Oncol. 2007; 25(33):5287-5312
5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (V.2.2011). January 5, 2011. For additional information: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.  Accessed on May 12, 2011

1. American Cancer Society. Detail Guide: Breast Cancer: What is breast cancer? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_breast_cancer_5.asp. Accessed on March 10, 2011.
2. National Cancer Institute. Breast Cancer Treatment. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page1. Accessed on May 12, 2011.
3. National Library of Medicine. Medical Encyclopedia: Breast Cancer. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000913.htm. Accessed on May 12, 2011.

Breast Cancer Risk Testing Network
Breast Cancer Gene Expression Ratio
H/I^SM
Insight^® DX Breast Cancer Profile
Mammaprint^®
Oncotype DX^®
The 76-gene "Rotterdam signature" assay
The 41-gene signature assay
Theros  H/I^SM
THEROS Breast Cancer Index^SM

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

STATEMENT OF MEDICAL NECESSITY for Oncotype DX for managing breast cancer

MEMBER INFORMATION

Name: _______________________________________   Member ID#:____________________

Date of Birth: _________________ Gender: ____ Female  _____ Male   Procedure Code: S3854

PHYSICIAN INFORMATION

Name: _______________________________________  Phone Number: ____________________

Address: _____________________________________________________________________

1. Member has had surgery and full pathological evaluation of the specimen has been completed Histology (please check applicable box): 
   

   _____	Ductal, or
   _____	Lobular, or
   _____	Mixed, or
   _____	Metaplastic, or
   _____	Not tubular or colloid

2. Was Estrogen receptor tested?___ Yes ___  No  If yes, what is result?                                                                              
3. Was Progesterone receptor tested? ___ Yes ___ No    If yes, what is result?                                                   
4. Was HER2 receptor tested? ___  Yes___  No   If yes, what is result? IHC:                              FISH:                                                 
5. pN0 (node negative) or pN1mi with axillary lymph node micrometastasis ≤ 2mm ___ Yes ___ No   
6. Please check the tumor size below
   

   _____	Tumor size < 0.6 cm
   _____	Tumor size 0.6-1.0 cm moderate/poorly differentiated or
   _____	Tumor size 0.6-1.0 cm and well-differentiated with any of the following unfavorable features: angiolymphaticinvasion, or high nuclear grade, or high histologic grade.
   _____	Tumor >1.0 cm and < 4.0 cm
   _____	Tumor size >4.cm

7. Is it a pT4 lesion?___ Yes  ___ No   

Chemotherapy is a therapeutic option being considered and would be supervised by the practitioner ordering the gene expression profile. ___ Yes ___ No   

Please refer to GENE. 00011 Gene Expression Profiling for Managing Breast Cancer Treatment.  This can be found on the plan web site.

This Statement of Medical Necessity form, with your completed responses, is not an authorization and is not intended as a substitute for, nor does it preclude, the Prior Authorization/ Pre-Certification requirements set forth in the member's benefit plan.   Once our review is complete, we will communicate our determination in accordance with our policies and procedures. In addition to this form, as evidenced above, the Health Plan may, in its sole discretion, request the complete medical record, or any part thereof during the evaluation for determination of medical necessity.

I do attest that the above is true and accurate to the best of my knowledge.

Physician Name (Print)______________________ Physician Signature:____________________ Date:________