Laboratory Section - Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis In Patients With Breast Cancer

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

For women with early stage breast cancer, adjuvant chemotherapy provides the same proportional benefit regardless of prognosis.  However, the absolute benefit of chemotherapy depends on the baseline risk for recurrence.  For example, women with the best prognosis have small tumors, are estrogen receptor positive, and lymph node negative.  These women have an approximately 15% baseline risk of recurrence; approximately 85% of these patients would be disease-free at ten years with tamoxifen treatment alone and could avoid the toxicity of chemotherapy if they could be accurately identified.  Conventional risk classifiers estimate recurrence risk by considering criteria such as tumor size, type, grade and histologic characteristics; hormone receptor status; and lymph node status.  However, no single classifier is considered a gold standard, and several common criteria have qualitative or subjective components that add variability to risk estimates.  As a result, more patients are treated with chemotherapy than can benefit.  Better predictors of baseline risk could help women who prefer to avoid chemotherapy if assured that their risk is low, make better treatment decisions in consultation with their physicians.

Recently, several groups have identified panels of gene expression markers (“signatures’) that appear to predict the baseline risk of breast cancer recurrence after surgery, radiation therapy, and hormonal therapy (for hormone receptor-positive tumors) in women with node-negative disease.  Five gene expression tests are commercially available in the U.S.:  Oncotype DX™ (a 21-gene RT-PCR assay; Genomic Health), the 70-gene signature MammaPrint® (also referred to as the “Amsterdam signature”; Agendia),  Mammostrat™ (developed by Applied Genomics Inc. and currently offered by the Molecular Profiling Institute), the Molecular Grade Index (Aviara MGISM; AviaraDx, Inc.) and the Breast Cancer Gene Expression Ratio (as originally offered by Quest Diagnostics under license; currently offered by AviaraDx, Inc. as Aviara H/ISM).  If these panels are more accurate than current conventional risk classifiers, they could be used to aid chemotherapy decision-making, where current guidelines do not strongly advocate its use, without negatively affecting disease-free and overall survival outcomes.

Of note, gene expression profiling should not be ordered as a substitute for standard estrogen receptor or progesterone receptor testing.   Gene expression profiles to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy should only be ordered after surgery and subsequent pathology examination of the tumor have been completed. The test should be ordered in the context of a physician-patient discussion regarding risk preferences and when the test result will aid the patient in making decisions regarding chemotherapy.

Note: This policy does not address the identification of germ-line alterations in genes (BRCA1 and BRCA2) to provide information on future risk of hereditary breast or ovarian cancer.  BRCA1 and BRCA2 testing is addressed in Regence Medical Policy, Laboratory, No. 10.

Policy/Criteria

1. The use of Oncotype DX™ in women with breast cancer to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary when all of the following characteristics are present:
   1. Unilateral, non-fixed tumor (i.e. tumor not adhered to the chest wall)
   2. Hormone receptor positive (that is ER-positive or PR-positive)
   3. HER2-negative
   4. Tumor size 0.6-1cm with moderate/poor differentiation or unfavorable features, OR tumor size > 1 cm.
   5. Negative lymph nodes  (nodes with micrometastases less than 2 mm in size are considered node negative)
   6. For patients who will be treated with adjuvant endocrine therapy, e.g., tamoxifen or aromatase inhibitors; AND
   7. For use when the test result will aid the patient in making the decision regarding chemotherapy (i.e., when chemotherapy is a therapeutic option).
2. Use of Oncotype DX™ to determine patient risk in those who have already made the decision to undergo chemotherapy is considered not medically necessary.
3. All other uses of Oncotype DX™, including but not limited to its use to predict response to specific chemotherapy regimens, are considered investigational.
4. Assays of genetic expression in breast tumor tissue with any other gene expression assay, including but not limited to MammaPrint®, Mammostrat™, the Molecular Grade Index (Aviara MGISM), or the Breast Cancer Gene Expression Ratio (Aviara H/ISM) are considered investigational.

Scientific Background

In February 2005, a TEC Assessment concluded that gene expression profiling for managing breast cancer treatment did not meet TEC criteria. (2) The TEC Assessment summarized the evidence for four different gene expression profiling assays, in various stages of development, that are intended for eventual use in identifying those patients at low risk of recurrence for whom adjuvant chemotherapy can be avoided. These are the 21-gene Oncotype DX™ (Genomic Health), the 70-gene MammaPrint® (Agendia; also referred to as the “Amsterdam signature”), the 76-gene “Rotterdam signature” (Veridex), and a 41-gene signature reported by Ahr et al. The TEC Assessment concluded that because published evidence supporting clinical utility is not available, the evidence for all of the gene expression panels was insufficient to permit conclusions concerning the effect of gene expression profiling on selecting patients who do not need chemotherapy for the purpose of avoiding adverse outcomes while maintaining or improving disease-free or overall survival outcomes.

In June of 2007 the original TEC Assessment was updated and limited to evaluation of the three gene expression profiles commercially available in the U.S. The objective of the updated Assessment was to determine whether, compared to conventional risk assessment tools, the use of gene expression profiling improves outcomes when used to decide whether risk of recurrence is low enough to forego adjuvant chemotherapy for early stage breast cancer. The evidence review is summarized below.

Oncotype DX™ (Genomic Health, Inc.)

Oncotype DX™ is available only from the CLIA-licensed Genomic Health laboratory as a laboratory-developed service. The test has not been cleared by the FDA; to date, FDA clearance is not required, although this may change if and when the FDA draft In Vitro Diagnostic Multivariate Index Assay (IVD-MIA) guidelines are finalized and published. Genomic Health indications for the test are newly diagnosed breast cancer patients with stage I or II disease that is node-negative and estrogen receptor-positive, and who will be treated with tamoxifen.

Results from the Oncotype DX™ gene expression profile are combined into a recurrence score (RS). Tissue sampling, rather than technical performance of the assay is likely to be the greatest source of variability in results. The Oncotype DX™ assay was validated in studies using archived tumor samples from subsets of patients enrolled in already-completed randomized controlled trials of early breast cancer treatment.

Validation and supportive studies delineating the association between RS and recurrence risk are shown in the Table (3-6). Results indicate strong, independent associations between Oncotype DX™ RS results and distant disease recurrence or death from breast cancer. (Table, 2, 5) In secondary analyses of the Paik et al. 2004a data (4,5), patient risk levels were individually classified by conventional risk classifiers, then re-classified by Oncotype DX™. Oncotype DX™ adds additional risk information to the conventional clinical classification of individual high-risk patients, and identifies a subset of patients who would otherwise be recommended for chemotherapy but are actually at lower risk of recurrence (average 7-9% risk at 10 years; upper 95% CI limits, 11-15%). Thus, a woman who prefers to avoid the toxicity of chemotherapy and inconvenience of chemotherapy and whose Oncotype DX™ RS value shows that she is at very low risk of recurrence might reasonably decline chemotherapy.  The lower the RS value, the greater the confidence that the woman can have that chemotherapy will not provide net benefit; outcomes are improved by avoiding chemotherapy toxicity.

An additional study, in which samples from a randomized controlled trial of ER-positive, node-negative breast cancer patients treated with tamoxifen vs. tamoxifen plus chemotherapy were tested by Oncotype DX™, provides supportive evidence. RS high-risk patients derived clear benefit from chemotherapy whereas the average benefit for other patients was statistically not significant, although the confidence intervals were wide and included the possibility of a small benefit (7).

The June 2007 Assessment concluded that Oncotype DX™ meets criteria for women with characteristics similar to those in the validation studies.  Patients in the validation studies were less than 70 years of age (or had a life expectancy of 10 years or more), had unilateral, non-fixed, estrogen-receptor (ER) positive, node-negative (by full axillary dissection) carcinomas and were treated with surgery (mastectomy or lumpectomy), radiation therapy, and tamoxifen. In one trial, patients in the experimental arm were also treated with CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy. Most (92%) patients were negative for HER-2 (3)

Because clinical care for breast cancer patients has evolved since the original trials from which archived samples were acquired for assay validation, differences in evaluation and treatment regimens were considered.  It was concluded that Oncotype DX™ meets the TEC criteria for the following women with node-negative breast cancer:

• Those receiving aromatase inhibitor (AI)-based hormonal therapy instead of tamoxifen therapy. AI-based therapy would likely reduce recurrence rates for all RS risk groups.  Thus, if a patients declined chemotherapy today on the basis of a low-risk RS (risk categories defined by outcomes with tamoxifen treatment), the even lower risk associated with AI treatment would not change that decision.
• Those receiving anthracycline-based chemotherapy instead of CMF.  The type of chemotherapy does not change the interpretation of the Oncotype DX™ risk estimate.  Additionally, a recent meta-analysis indicates that anthracyclines do not improve disease-free or overall survival in women with early, HER2-negative breast cancer (8), and therefore may not be prescribed in this population.
• Lymph nodes with micrometastases are not considered positive for purposes of treatment recommendations. (9) Current practice largely involves a detailed histologic examination of sentinel lymph nodes allowing for the detection of micrometastases (less than 2 mm in size).
• Those whose tumors are ER-positive or PR-positive.  Only ER-positive women were enrolled in Oncotype DX™ validation studies whereas current clinical guidelines include either ER or progesterone receptor (PR) positivity in the treatment pathway for hormone receptor positive women with early stage breast cancer.  Recent studies show that ER-negative, PR-positive patients also tend to benefit from hormonal therapy. (10, 11)

For hormone receptor-positive, HER2-negative early breast cancer patients the 2008 National Comprehensive Cancer Network (NCCN) guidelines (9) indicate that Oncotype DX may be considered in patients whose tumors are node-negative, hormone-receptor-positive, HER2-negative, and 0.6-1cm in size with moderate/poor differentiation or unfavorable features OR >1cm in size. NCCN does not suggest Oncotype DX for HER2 positive tumors. Because HER2 is represented in the Oncotype DX panel and RS results for HER2-positive patients are likely to be categorized as intermediate or high risk; this was true of all of the 55 HER2-positive patients in the first Oncotype DX validation study (3).

The 2007 American Society of Clinical Oncology (ASCO) guidelines (12) indicate 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.” In contrast, the St. Gallen expert consensus panel “did not accept the molecularly based tools such as Oncotype DX™. . . as sufficiently established to define risk categories.” (13)

Limitations of the current evidence, such as confirmation of optimal RS cutoff values for tamoxifen-treated and separately for AI-treated patients and recommendations for patients with intermediate RS values, are likely to be answered by the results of the ongoing Trial Assigning Individual Options for Treatment (Rx), also known as TAILORx.

In June, 2008, Genomic Health announced that results of Oncotype DX™ tests would include not only the overall test results, but also the results of the quantitative ER and progesterone receptor (PR) tests that are included in the Oncotype DX™ panel. This is based on a study published in May 2008, that compared the Oncotype DX™ ER and PR results to traditional immunohistochemistry (IHC) results. (14) The study reported high concordance between the two assays (90% or better), but that quantitative ER by Oncotype DX™ was more strongly associated with disease recurrence than the IHC results. However, ER and PR analysis is traditionally conducted during pathology examination of all breast cancer biopsies, whereas Oncotype DX is indicated only for known ER-positive tumors, after the pathology examination is complete, the patient meets specific criteria, and patient and physician are considering preferences for risk and chemotherapy. Thus, Oncotype DX™ should not be ordered as a substitute for ER and PR IHC.

The 2005 TEC Assessment also evaluated studies of Oncotype DX™ for use in predicting response to specific chemotherapy regimens and found the evidence insufficient for conclusions. These studies were reviewed and the search updated for this policy review ( 15, 16); no published studies were found that changed these conclusions.  An abstract presented at the 2007 Annual San Antonio Breast Cancer Symposium reported on the use of the test in predicting response to doxorubicin-based chemotherapy (17). Evaluation of this study awaits publication. In addition, Goldstein has reported on use of the 21-gene assay in a sample of patients, 44% of whom had one to three positive nodes, and all of whom were treated with chemohormonal therapy. (18) This study found that RS was a highly-significant predictor of recurrence for node-negative and node-positive disease. The authors concluded that both RS and standard clinical and pathological features contribute significantly and independently to recurrence prediction. The findings also suggest that it may be possible to withhold adjuvant chemotherapy from patients with one to three positive axillary lymph nodes with low RS. However, as the authors note, because there was no arm without chemotherapy treatment, it is not possible to directly evaluate whether the excellent outcome in those with low RS was related to good prognosis, chemotherapy benefit, or both.  Therefore, additional, properly designed studies are needed to support this indication. Thus, no changes are made to the policy statement concerning node status.

Abbreviations:

CI - confidence interval; DRF - distant recurrence free; ER - estrogen receptor; N - total number of patients; NR - not reported; RS - Oncotype DX recurrence score; K-M - Kaplan Meier; NSABP - National Surgical Adjuvant Breast and Bowel Project; RCT - randomized controlled trial; TAM - tamoxifen; NCCN - National Comprehensive Cancer Network.

¹Percentages are percent of total N.

MammaPrint®

The 2007 TEC Assessment reviewed available studies ( 19-23) and found insufficient evidence to determine whether MammaPrint® is better than conventional risk assessment tools in predicting recurrence. Limited technical performance evaluation of the commercial version of the assay suggests good reproducibility. Recurrence rates of patients classified as low risk in available studies were 15-25%, likely too high for most patients and physicians to consider forgoing chemotherapy.  Similarly, in one study, after Adjuvant risk classification, patients reclassified as low risk by the 70-gene signature in either Adjuvant risk group had 10-year disease-free survival rates of 88–89%, with lower confidence limits of 74-77%. Patients reclassified as high risk had 10-year disease-free survival rates of 69%, with lower confidence limits of 45–61% and upper confidence limits of 76–84%  ; ROC analysis suggests only a small improvement with MammaPrint® classification compared to a conventional classifier.(19) Because initial studies had been conducted on samples from younger patients (age less than 61), Wittner et al. studied a cohort of 100 lymph-node-negative patients with a median age of 62.5 years and a median follow-up of 11.3 years (24). Only 27 patients were classified low-risk by MammaPrint, but distant metastasis-free survival at 10 years was 100%. For the 73 patients classified as high risk, distant metastasis-free survival at 10 years was about 90% but there was no statistically significant difference in survival between the low- and high-risk groups. The patients studied were heterogeneous in terms of ER-positivity (73%), hormonal therapy (25%), and chemotherapy (23%); subpopulations were too small for separate evaluation of outcomes. Thus, the published evidence remains insufficient for recommendations on how to use the test to direct treatment and improve outcomes.

Breast Cancer Gene Expression Ratio (Aviara H/ISM)

The 2007 TEC Assessment reviewed available studies (25-30) and found insufficient evidence to determine whether the Breast Cancer Gene Expression Ratio is better than conventional risk assessment tools in predicting recurrence. Assay configuration and performance characteristics of the commercially available version of the test have not been published. Recurrence rates of patients classified as low risk in available studies were 17-25%, likely too high for most patients and physicians to consider forgoing chemotherapy. There are no reclassification studies to directly compare the Breast Cancer Gene Expression Ratio with conventional risk classifiers.

The Molecular Grade Index (Aviara MGISM)

MGI stands for molecular grade index; the assay is intended to measure tumor grade using the expression of five cell cycle genes and provide prognostic information in ER-positive patients regardless of nodal status. Ma et al. evaluated MGI along with Aviara H/ISM in a total of 733 patients (31). High MGI was associated with significantly worse outcome only in patients with high Aviara H/ISM and vice versa. Both assays are offered separately; the utility of MGI alone is unclear. There are no reclassification studies of comparison with conventional risk classifiers.

Mammostrat™

Mammostrat™ is an IHC test intended to evaluate risk of breast cancer recurrence in postmenopausal, node negative, estrogen receptor-positive breast cancer patients who will receive hormonal therapy and are considering adjuvant chemotherapy. The test employs five monoclonal antibodies to detect gene expression of proteins involved in various aspects of cell proliferation and differentiation and a proprietary diagnostic algorithm to classify patients into high-, moderate-, or low-risk categories. One study reports the development of the assay but provides no information on technical performance (analytic validity). (32) In an independent cohort, a multivariable model predicted 50%, 70%, and 87% 5-year disease-free survival for patients classified as high, moderate, and low prognostic risk, respectively, by the test results (p=0.0008). There are no published reclassification studies of comparison with conventional risk classifiers.

Guidelines

Neither the NCCN, nor ASCO or St. Gallen guidelines support any indications for the use of MammaPrint®, Aviara MGISM, the Breast Cancer Gene Expression Ratio (Aviara H/ISM), or Mammostrat™. (9,12,13)

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.36
2. BlueCross and BlueShield Association Technology Evaluation Center Assessment. Gene expression profiling for managing breast cancer treatment, 2005 TEC Assessment  Vol.20 Tab 3
3. Paik S, Shak S, Tang G, et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.  NEJM  2004a;351(27):2817-26
4. 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, 2004b;88(Suppl 1):A104 [Abstract]
5. Bryant J. Toward a more rational selection of tailored adjuvant therapy data from the National Surgical Adjuvant Breast and Bowel Project. 2005 St. Gallen Breast Cancer Symposium. [Complete slide presentation via Genomic Health]
6. Habel LA, Quesenberry CP, Jacobs MK et al. (2006). A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res, 8(3):R25. Epub 2006 May 31
7. Paik S, Tang G, Shak S et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol, 2006;24(23):3726-34
8. Gennari A, Sormani MP, Pronzatov P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: A pooled analysis of randomized trials. J Natl Cancer Inst 2008;100:14 – 20
9. National Comprehensive Cancer Network. Practice Guidelines in Oncology: Invasive Breast Cancer. 2008. Accessible at: www.nccn.org  (Verified 2/16/09)
10. Dowsett M, on Behalf of the ATAC Trialists Group. Analysis of time to recurrence in the ATAC (arimidex, tamoxifen, alone or in combination) trial according to estrogen receptor and progesterone receptor status.  26th Annual San Antonio Breast Cancer Symposium, 2003
11. Dowsett M, Houghton J, Iden C et al. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according to oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol 2006;17(5):818-26
12. 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):5287-312
13. Goldhirsch A, Wood W, Gelber R et al. Progress and promise: Highlights of the international expert consensus on the primary therapy of early breast cancer 2007.  Ann Oncol 2007;18(7):1133-44
14. Badve SS, Baehner FL, Gray RP et al. Estrogen- and progesterone-receptor status in ECOG 2197: comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. J Clin Oncol 2008;26(15):2473-81
15. Gianni L, Zambetti M, Clark K et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-77
16. Mina L, Soule SE, Badve S et al. Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue. Breast Cancer Res Treat, 2007;103(2):197-208
17. Albain K, Barlow W, Shak S et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (S8814,INT0100). 2007 Annual San Antonio Breast Cancer Symposium, Abstract #10
18. Goldstein LJ, Gray R, Badve S et al. Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol 2008; 26:4063-71
19. van de Vijver, 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
20. 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):530-6
21. Espinosa E, Vara JA, Redondo A et al. Breast cancer prognosis determined by gene expression profiling: a quantitative reverse transcriptase polymerase chain reaction study. J Clin Oncol, 2005;23(29):7278-85
22. Buyse M, Loi S, van't Veer L et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst, 2006;98(17):1183-92
23. Glas AM, Floore A, Delahaye LJ et al. Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 2006;7:278
24. 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):2988-93
25. Goetz MP, Suman VJ, Ingle JN et al. A two-gene expression ratio of homeobox 13 and interleukin-17B receptor for prediction of recurrence and survival in women receiving adjuvant tamoxifen. Clin Cancer Res, 2006;12(7 Pt 1):2080-7
26. Ma XJ, Hilsenbeck SG, Wang W et al. The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer. J Clin Oncol, 2006;24(28):4611-9
27. Ma XJ, Wang Z, Ryan PD et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell, 2004;5(6):607-16
28. Reid JF, Lusa L, De Cecco L et al. Limits of predictive models using microarray data for breast cancer clinical treatment outcome. J Natl Cancer Inst, 2005;97(12):927-30
29. Jansen MP, Sieuwerts AM, Look MP et al. HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: a retrospective study. J Clin Oncol 2007;25(6):662-8
30. Jerevall PL, Brommesson S, Strand C et al. Exploring the two-gene ratio in breast cancer-independent roles for HOXB13 and IL17BR in prediction of clinical outcome.  Breast Cancer Res Treat 2008; 107(2):225-34
31. Ma XJ, Salunga R, Dahiya S et al. A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin Cancer Res 2008; 14(9):2601-8
32. 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):3039-47

Cross References

Genetic Testing. Regence Medical Policy Manual, Laboratory, Policy No. 20

Regence Consumer Tx: Breast Cancer - Gene Expression Profile Testing

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