BlueCross and BlueShield of Montana Medical Policy/Codes
Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Cancer
Chapter: Medicine: Tests
Current Effective Date: October 25, 2013
Original Effective Date: September 01, 2007
Publish Date: October 25, 2013
Revised Dates: March 5, 2010; October 12, 2011; September 3, 2013
Description

Generally gene expression is the process by which information from a gene is used in the synthesis of a functional gene product.  The genetic code is “interpreted” by gene expression, and the properties of the expression products give rise to the organism’s phenotype, which is the observable characteristic or trait of an organism.  Measuring gene expression, the ability to quantify the level at which a particular gene is expressed within a cell, tissue, or organism can provide additional information.  Of late, the acceleration of gene expression profiling research has made available additional markers to predict disease recurrence in breast and colon cancer patients.  Determination of an individual’s susceptibility to cancer is known as oncogene expression.  

Breast Cancer:

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 of recurrence.  Patients with the same set of risk factors can have markedly different prognoses.  For example, not all patients with positive large breast tumors or positive axillary lymph nodes are destined to progress to metastatic disease, and yet adjuvant chemotherapy is routinely recommended in all of these patients.  A set of more sensitive and specific risk factors would improve patient selection criteria for adjuvant therapy and other aspects of the treatment of breast cancer.  Women with the best prognosis have small tumors, are ER+, 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.  Currently, conventional risk classifiers and prognosis in breast cancer is based on patient age, tumor size, histology, status of the axillary lymph nodes, histologic type and grade, and hormone receptor 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 or “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 (Applied Genomics, Inc.), the Molecular Grade Index (Aviara MGISM; AviaraDx, Inc.) and the THEROS Breast Cancer Index.  If these panels are more accurate than current conventional classifiers, they could be used to aid chemotherapy decision-making, without negatively affecting disease-free and overall survival outcomes.

Colon Cancer:

A 12-gene expression test (Oncotype DX Colon Cancer Assay; Genomic Health) has been developed to predict the likelihood of disease recurrence for patients with stage II colon cancer following surgery.  Colorectal cancer is classified stage II when it has spread outside the colon and/or rectum to nearby tissue, but is not detectable in the lymph nodes and has not metastasized to distant sites (also called Dukes B).  The primary treatment is surgical resection of the primary cancer and colonic anastomosis.  After surgery the prognosis is very good, with survival rates of 75% to 80% at five years. 

Of patients with stage II colon cancer, 75–80% are cured by surgery alone, and the absolute benefit of chemotherapy for the patient population is small.  Those patients who are most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathological risk factors.  The 12-gene expression test is intended to be used as an aid in identifying those stage II patients most likely to experience recurrence after surgery and therefore those most likely to benefit from additional treatment.

Other Forms of Cancer:

Utilization of gene expression testing is under development for other forms of cancer, including non-small cell lung cancer.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Breast Cancer:

The use of 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) assay (i.e., Oncotype DX® Breast Cancer Assay) to determine risk of breast cancer recurrence and guide the physician and patient decision making on adjuvant chemotherapy may be considered medically necessary when ALL of the following criteria are met:

A.  Completion of surgery and subsequent pathology examination of the tumor; AND

B.  The test is ordered on a tissue specimen obtained during surgical removal of the tumor; AND

C.  The test is ordered by the oncologist who is caring for the patient; AND

D.  There is documented physician-patient discussion about how those results will guide the patient in decision-making on chemotherapy; AND

E.  The patient’s breast cancer will be treated with hormonal therapy; AND

F.  The cancer has the following characteristics:

  • Unilateral, non-fixed tumor, AND
  • Hormone-receptor-positive (ER-positive [estrogen receptor positive, ER+] or PR-positive [progesterone receptor positive, PR+]), AND
  • HER2- (human epidermal growth factor receptor 2-) negative, AND
  • Tumor size of either:
    1. 0.6-1 cm with moderate, poor differentiation, or unfavorable features, OR
    2. >1 cm,

              AND

  • Lymph node-negative (including lymph nodes with micrometastases smaller than 2 mm size).

NOTE:  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 breast tumor, as the treatment is based on the most aggressive lesion.

The use of the 21-gene RT-PCR assay Oncotype DX testing for breast cancer is considered not medically necessary when done on a preliminary core breast biopsy.

All other indications for the 21-gene RT-PCR assay Oncotype DX, including but not limited to the determination of recurrence risk in breast cancer patients who are lymph node-positive, are considered experimental, investigational and unproven

The use of MammaPrint®, Mammostrat®, or THEROS Breast Cancer IndexSM® (formerly Aviara MGISM [Molecular Grade Index]) for any indication is considered experimental, investigational and unproven

Colon Cancer:

The use of 12-gene expression test (Oncotype DX Colon Cancer Assay) is considered experimental, investigational and unproven, including but not limited to use for predicting the likelihood of disease recurrence in patients with stage II colon cancer following surgery.

Other Forms of Cancer:

The use of gene expression testing is considered experimental, investigational and unproven for all forms of cancer not listed above, including but not limited to non-small cell lung cancer.

Policy Guidelines

There are no specific CPT or HCPCS codes for this laboratory test.  Effective 2006, HCPCS code S3854 may be used to report a gene expression profile panel to assist in breast cancer therapy management.

Rationale

Breast Cancer:

A variety of studies have explored the feasibility of developing assays for genetic expression as a prognostic factor for breast cancer and other tumors, but a literature search did not find any prospective studies that used this information in the management of the patient.  Specifically, there is no published data showing that this technology can be used either to select or deselect patients for adjuvant therapy after primary surgical excision of breast cancer.

The published literature primarily consists of validation studies to identify the optimal set of cancer-related genes.  For example, tumor tissue can be retrieved from stored paraffin blocks of resected breast cancer and analyzed for patterns of genetic expression, which are then correlated with the patients’ outcomes and recorded in patient registries.  In an initial study, Van de Vijver and colleagues developed a classification system of genetic expression that outperformed all clinical variables in predicting the likelihood of developing distant metastases within five years.  This genetic “signature” was then assayed in 295 patients with Stage I or II breast cancer; 151 had lymph node-negative disease and 144 had positive nodes.  The median duration of follow-up was 7.8 years for those who did not develop metastases.  Patients assigned to a low-risk group by gene expression had a higher likelihood of metastasis-free survival than those classified by conventional criteria.  Similarly, patients assigned to high-risk groups by gene expression had a higher risk of distant metastases than those classified conventionally.  The authors concluded that the gene expression profile was a more powerful predictor of the outcome of disease than standard systems using clinical and histological criteria.

Two abstracts of validation studies were presented at the 2003 annual meeting of the American Society of Clinical Oncology (ASCO).  Esteban and colleagues retrieved tumor tissue from paraffin-embedded pathology specimens of 146 patients with breast cancer.  The tumor tissue was evaluated for the expression of 185 cancer-related genes, and a number of genes were identified that were associated with either increased or decreased disease-free survival (DFS).  Using a similar panel of cancer genes, Cobleigh and colleagues analyzed tumor tissue from a group of 79 patients with 10 or more positive lymph nodes.  Similarly, expression of different genes was associated with either shorter or longer DFS.  Finally, using the above two studies as a reference, Paik and colleagues reported on a further validation study in 242 patients with node-negative breast cancer.  Patients were identified from the databases and stored pathology specimens from prior National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials focusing on patients with ER+ and node-negative tumors. One of the purposes of the study was to identify a single multi-gene assay that could be subjected to formal clinical validation.  Analysis indicated that of the 185 genes tested, 41 were associated with relapse-free survival.  Many of the genes were closely correlated, and ultimately the authors identified a single multi-gene model containing 21 genes.  This 21-gene predictor for likelihood of disease is currently being prospectively studied in a formal clinical validation study of over 500 patients, but results of this study have not yet been published.

In February 2005, a Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment concluded that gene expression profiling for managing breast cancer treatment did not meet the BCBSA TEC Assessment criteria.  The BCBSA 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 were the 21-gene Oncotype DX of Genomic Health, MammaPrint of Agendia, the 76-gene “Rotterdam signature” of Veridex, and a 41-gene signature reported by Ahr et al.  The BCBSA TEC Assessment concluded that because published evidence supporting clinical utility was not available, the evidence for all of the gene expression panels was insufficient.

A 2006 abstract described a study of the 21-gene recurrence score (RS) assay that quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with tamoxifen, with or without chemotherapy.  The RS was measured in the NSABP B20 trial, where 651 patients were randomly assigned to tamoxifen (n=227) or to tamoxifen plus chemotherapy (n=424).  Patients, with a high-RS tumor (i.e., high-risk of recurrence), had a large benefit from chemotherapy (relative risk, 0.26; 95% cancer index, 0.13 to 0.53; absolute decrease in ten-year distant recurrence rate; mean 27.6%; side effects 8.0%) .  Whereas, patients with a low-RS tumor derived a minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% cancer index, 0.46 to 3.78; absolute decrease recurrence rate at ten-years; mean, -1.1%; side effects, 2.2%).  Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. 

In June of 2007 the original BCBSA TEC Assessment was updated and limited to evaluation of the three gene expression profiles commercially available in the U.S. (Oncotype DX, MammaPrint, and a new test called the Breast Cancer Gene Expression Ratio).  The objective of the updated BCBSA TEC Assessment was to determine whether, compared to conventional risk assessment tools, the use of gene expression profiling improves outcomes when used to decide if risk of recurrence is low enough to forego adjuvant chemotherapy for early stage breast cancer.  The evidence review is summarized below.

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 U.S. Food and Drug Administration (FDA); to date, FDA clearance is not required, although this may change if and when the FDA draft guidelines In Vitro Diagnostic Multivariate Index Assay (IVDMIA) 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 ER+, and who will be treated with tamoxifen.  Results from the Oncotype DX 21-gene expression profile are combined into a 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 below.  Results indicate strong, independent associations between Oncotype DX RS results and distant disease recurrence or death from breast cancer.  In secondary analyses of the Paik et al. 2004 data, patient risk levels were individually classified by conventional risk classifiers, and 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 who are actually at lower risk of recurrence (average 7-9% risk at ten-years; upper 95% confidence interval [CI] limits, 11-15%).  Thus, a woman who prefers to avoid the toxicity 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 the woman can have that chemotherapy will not provide net benefit; outcomes are improved by avoiding chemotherapy toxicity.

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

The September 2007 BCBSA TEC Assessment concluded that Oncotype DX meets criteria for women similar to those in the validation studies.  Patients in the validation studies include those who:

  • were less than 70 years of age (or had a life expectancy greater than ten years),
  • had unilateral, non-fixed, ER+, lymph 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) or MF (methotrexate and 5-fluorouracil) chemotherapy.  Most patients (92%) were negative for HER2-.

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 BCBSA TEC Assessment criteria for the following women with lymph 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 patient 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 population.
  • Those whose lymph nodes with micrometastases are not considered positive for purposes of treatment recommendations.  Current practice largely involves a detailed histologic examination of sentinel lymph nodes allowing for the detection of micrometastases (less than two millimeters [mm] in size).
  • Those whose tumors are ER+ or PR+.  Only ER+ women were enrolled in Oncotype DX validation studies whereas current clinical guidelines include either ER or progesterone receptor positivity in the treatment pathway for hormone receptor positive women with early breast cancer.  Recent studies show that ER-, PR+ patients also tend to benefit from hormonal therapy.

For hormone receptor-positive, HER2-negative early breast cancer patients the 2008 National Comprehensive Cancer Network (NCCN) guidelines indicate that Oncotype DX may be considered in patients whose tumors are lymph 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.

The 2007 ASCO guidelines 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.” The 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 Individualized Options for Treatment (Rx), also known as TAILORx.

The 2005 BCBSA 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; no studies were found that changed these conclusions.

Summary of Oncotype DX - RS and Recurrence Risk Studies.

Study

Study Type

Total N

Study Objective

Results

Paik, et al. 2004

 

TAM arm of NSABP

B-14 RCT

668

Predict recurrence

 

 RS Risk

% of Patients

K-M Distant recurrence of 10 yr.% (95% CI)

Low (<18)

Intermed (18–30)

High (>31)

51

22

27

6.8

14.3

30.5

(4.0–9.6)

(8.3–20.3)

(23.6–37.4)

All

100

15

(12.5–17.9)

 

Paik, et al. 2004

 

Additional analysis of Paik, et al. 2004 data

668

Reclassification study; determine incremental risk compared to conventional classifier

Risk Classification by:

 

N

% DRF at 10 year (95% CI2)

NCCN

Oncotype

Low (8%)

Low

Intermed

High

38

12

2

100 (NR)

80 (59–100)

56 (13–100)

High (92%)

Low

Intermed

High

301

137

178

93 (89–96)

86 (80–92)

70 (62–77)

Bryant 2005

 

Additional analysis of Paik, et al. 2004a data

668

Reclassification study; determine incremental risk compared to conventional classifier

 Risk Classification by:

 

N

% DRF at 10 year (95% CI2)

Adjuvant Online1

Oncotype

Low (53%)

Low

Int-Med

214

140

5.6 (2.5-9)

12.9 (7-19)

Intermed-High (47%)

Low

Int-Med

120

194

8.9 (4-14)

30.7 (24-38)

Habel, et al. 2006

 

Case-control

255 ER+ TAM+;

361

ER+ TAM-

Predict mortality

 

 RS Risk

10-yr Absolute Risk of Death, % (95% CI)

ER+, TAM-treated

ER+, No TAM

 

Low (<18)

Int (18–30)

High (>31)

2.8

(1.7–3.9)

10.7

(6.3–14.9)

15.5

(7.6–22.8)

6.2

(4.5–7.9)

17.8

(11.8–23.3)

19.9

(14.2–25.2)

Abbreviations:

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 (2004);

Int/Intermed, Intermediate.

Table Notes:

1Percentages are percent of total N.

2Estimated from graphs.

(Note that different outcomes were reported between Paik, et al.. 2004b and Bryant 2005 and could not be converted to similar outcomes with CI.)

The 2007 BCBSA TEC Assessment reviewed available studies 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.  There are no reclassification studies; receiver operating characteristic (ROC) analysis suggests only a small improvement with MammaPrint classification compared to a conventional classifier.

The 2007 BCBSA TEC Assessment reviewed available studies 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.

Neither the NCCN, ASCO, nor St. Gallen guidelines support any indications for the use of MammaPrint or the Breast Cancer Gene Expression Ratio.

2010 Update

The 2009 NCCN guidelines indicate that Oncotype DX may be “considered” in breast cancer patients with the following characteristics:

  • Hormone-receptor-positive;
  • HER2-negative;
  • Lymph node-negative OR not greater than 2 mm axillary node metastasis; AND
  • Size of 0.6–1 cm and moderate/poorly differentiated or unfavorable features OR size larger than 1 cm.

NCCN does not suggest Oncotype DX for HER2-positive tumors.  Because HER2- is represented in the Oncotype DX panel, 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.

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 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.  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.

A study reported at the 2008 Annual San Antonio Breast Cancer Symposium evaluated samples from the Southwest Oncology Group Trial 8814, in which randomized lymph node-positive, ER+ patients treated with tamoxifen for five years were compared to those treated with cyclophosphamide, doxorubicin, fluorouracil (CAF) chemotherapy followed by tamoxifen (CAF-T) for five years.  Samples were available for determination of Oncotype DX RS for 41% (n=148) and 39% (n=219) of the trials arms, respectively.

In this study, ten-year DFS and overall survival (OS) outcomes in the tamoxifen study arm differed by RS risk category (p=0.017 and 0.003, respectively), indicating that the RS is prognostic.  When the two treatment arms were compared within RS risk categories, only patients in the high RS category significantly benefited from the addition of CAF to tamoxifen (for DFS, 42% [tamoxifen] vs. 55% [CAF-T], p=0.033; for OS, 51% [tamoxifen] vs. 68% [CAF-T], p=0.027), suggesting that RS is also predictive of response to chemotherapy.

A multivariable analysis of RS interaction with DFS, adjusted for number of positive nodes, was significant for the first five years of follow-up at p=0.029, and remained significant after adjusting for age, race, tumor size, progesterone receptor status, grade, p53, and HER2-. However, the interaction was not significant (p=0.15) after adjusting for ER level (ER gene expression is a component of the Oncotype DX Breast Cancer Assay).  Interaction results were similar for OS.  Therefore, this study suggests that in women with lymph node-positive, ER+ breast cancer, the Oncotype DX RS may help identify those women who are unlikely to benefit from the addition of CAF chemotherapy to their treatment regimen.  However, the study has not yet been published in a peer-reviewed journal.

A previous study by Chang et al., not designed to validate Oncotype DX, reported that in women with locally advanced breast cancer treated with neoadjuvant docetaxel (n=97), a complete response was more likely in those with a high RS (p=0.008).  Gianni et al. studied 93 patients who received neoadjuvant taxane chemotherapy, then post-surgery CMF treatment and tamoxifen (if ER+).  The authors reported that pathological complete response was more likely in patients with high RS results than with low RS results (p<0.01).

Additional studies are necessary before it is possible to confidently withhold previously recommended chemotherapy from lymph node-positive breast cancer patients with low/intermediate RS results.  Under an award from the National Cancer Institute, the Fred Hutchinson Cancer Research Center will investigate the predictive ability of Oncotype DX test to determine which lymph node-positive breast cancer patients will benefit from chemotherapy treatment. The study is described as a prospectively designed follow-up to an already completed trial conducted in the lymph node-positive population.

Additional Genetic Expression Testing Reviewed:

  • MammaPrint has received 510(k) clearance for marketing by the FDA; it is a prognostic test for women younger than 61 years with ER+ or ER-, lymph node-negative breast cancer.  The 2007 BCBSA TEC Assessment reviewed available studies 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! Online (a web site to help health professionals and patients assess risks and benefits of additional therapy) risk classification, patients reclassified as low-risk by the 70-gene signature in either Adjuvant! risk group had ten-year DFS rates of 88%–89%, with lower CI limits of 74%–77%.  Patients reclassified as high-risk had ten-year DFS rates of 69%, with lower CI limits of 45%–61% and upper CI limits of 76%–84%; ROC analysis suggests only a small improvement with MammaPrint classification compared to a conventional classifier.

Because initial studies had been conducted on samples from younger patients (age younger 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.  Only 27 patients were classified low-risk by MammaPrint, but distant metastasis-free survival at ten years was 100%.  For the 73 patients classified as high-risk, distant metastasis-free survival at ten 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.

Three studies of MammaPrint were published in 2009.  One small (n=123) study of lymph node-negative patients younger than 55 years, 76% with ER+ tumors, who received variable treatment for early-stage breast cancer, reported that the 70-gene signature was significant in multivariate analyses for prognosis.  However, the small study size and small number of events precludes an adequate statistical analysis.  Use of the gene signature increases the AUC (area under the ROC curve) in an ROC analysis, but 95% CI overlap. Finally, a classification comparison with Adjuvant! reported only discordance, not reclassification outcomes.  This study also updated results of the lymph node-negative population from the validation study, reporting significantly different outcomes for good and poor gene signature prognosis groups, but estimates were very wide due to small numbers and an ROC analysis also showed overlapping CI.  Thus, the published evidence remains insufficient for recommendations on how to use the test to direct treatment and improve outcomes in patients with lymph node-negative disease.

Mook et al. studied 241 lymph node-positive patients with primarily ER+, HER2-negative tumors treated variably.  The 70-gene signature was a significant predictor of outcome overall and in individual treatment groups, but estimates had wide CI due to small numbers. Classification of patients by Adjuvant!, then reclassification by MammaPrint showed additional discrimination of outcomes by the gene signature, but results were confounded by heterogeneous patient treatment.  This study also updated lymph node-positive patients from the validation study, reporting 98% breast cancer-specific survival for good prognosis signatures vs. 64% for poor prognosis signatures; adjusted HR 3.63 (0.88–14.96), p=0.07.  Based on these results, the ongoing MINDACT (Microarray In Node-negative Disease may Avoid Chemo-Therapy) trial of MammaPrint is being enlarged to include patients with one to three positive lymph nodes.

A third study of patients with heterogeneous tumors and receiving neoadjuvant treatment reported preliminary data that patients with good prognosis signatures did not benefit from neoadjuvant treatment and were less likely to relapse.

  • The THEROS Breast Cancer Index is a simultaneous assessment of THEROS H/ISM (H/I measures the Ratio of HOXB13:IL17BR, formerly Aviara H/ISM) and THEROS MGISM (Molecular Grade Index [MGI], formerly Aviara MGISM).  The 2007 BCBSA TEC Assessment reviewed available studies for the original component assays.  There was insufficient evidence to determine whether the H/I 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 H/I Ratio with conventional risk classifiers.  The MGI 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 H/I Ratio in a total of 733 patients.  High MGI was associated with significantly worse outcome only in patients with high H/I Ratio and vice versa.  There are no reclassification studies of comparison with conventional risk classifiers; thus, clinical utility is unclear.
  • Mammostrat is an immunohistochemistry (IHC) test intended to evaluate risk of breast cancer recurrence in postmenopausal, lymph node-negative, ER+ 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).  In an independent cohort, a multivariable model predicted 50%, 70%, and 87% five year decision support framework (DSF) for patients classified as high-, moderate-, and low-prognostic-risk, respectively, by the test results (p=0.0008).  An additional study of the same trial samples used for Oncotype DX validation (NSABP B-14 and B-20 trials) reported that among patients with early, lymph node-negative breast cancer treated only with tamoxifen, those stratified by Mammostrat into low-, moderate-, and high-risk groups had recurrence-free survival estimates of 85%, 85%, and 73%, respectively. Both low- and high-risk groups, but not moderate-risk groups, benefited significantly from chemotherapy treatment.  A test for an interaction between chemotherapy and the risk group stratification was not significant (p = 0.13).  There are no published reclassification studies of comparison with conventional risk classifiers.

Therefore, neither the NCCN nor the ASCO support any indications for the use of MammaPrint, THEROS Breast Cancer Index, or Mammostrat.  The St. Gallen guidelines refer to the use of validated, multigene assays in specific situations but do not name any specific assays.

Summary

In conclusion, the studies identified, via a search of peer reviewed literature, through September 2010 did not lead to a change in the coverage position, specific to breast cancer, of this medical policy.

Colon Cancer:

The 12-gene expression test was launched by Genomic Health as the Oncotype DX Colon Cancer Assay in January 2010.  The test has not been submitted to or cleared for marketing by the U.S. FDA.  The test is offered as a laboratory-developed assay service conducted in the CLIA-licensed Genomic Health clinical laboratory.

Development of the 12-gene expression test has been briefly described in abstracts presented at the annual meetings of ASCO in 2009-2010.  A total of 761 candidate genes of possible prognostic value for recurrence or of possible predictive value for treatment were examined by correlating the genes in tumor samples with the clinical outcomes seen in 1,851 patients who had surgery with or without adjuvant 5-fluorouracil-based chemotherapy.  Gene expression was quantitated from microdissected fixed paraffin-embedded primary colon cancer tissue.  Of the 761 candidate genes surveyed, a multivariate analysis including disease severity, stage, and nodal involvement, reduced the genes to a significant seven-gene prognostic signature and a separate six-gene predictive signature.  Five reference genes are also included in the assay.

The prognostic and predictive signatures were independently evaluated using tumor samples of a stage II subset of patients from the Quick and Simple and Reliable (QUASAR) study; the subset represented 44% of the entire parent study population and included 711 patients treated with surgery alone and 725 patients treated with adjuvant 5-fluorouracil-based chemotherapy following surgery with a mean follow-up of approximately seven years.

The seven-gene prognosis signature, reported as an RS, was a significant and independent predictor of three year recurrence risk, which increased continuously with RS.  RS scores could separate patients into low-, intermediate-, and high-risk groups.  Recurrence risks (95% CI) of disease at three years for the low-, intermediate-, and high-risk groups were 12% (9–16%), 18% (13–24%), and 22% (16–29%), respectively.  Additional study of the QUASAR data showed that RS and number of lymph nodes examined were independent predictors, with three year recurrence risk approximately 5% lower when 12 or more compared to when fewer than 12 nodes were examined.  Another report compared pathologic markers and gene expression by stage for both stage II and III patients in the four studies conducted to develop the Oncotype DX Colon Cancer Assay.  Neither RS nor the majority of genes examined showed significant interaction with stage, indicating a need to examine predictors of recurrence risk in stage III as well as stage II disease.

The six-gene predictive signature for 5-fluorouracil chemosensitivity did not show significance in the validation study.

On January 21, 2010, Genomic Health announced the worldwide commercial availability of its Oncotype DX Colon Cancer Assay.  As stated in the press release, “The 12-gene advanced diagnostic test is clinically validated to predict individual recurrence risk in stage II colon cancer patients following surgery.”  It is assumed that the test consists of the seven-gene prognostic score plus the five reference genes and that the six-gene predictive signature for chemosensitivity has been removed; however, no details are available on the web site.

This review of evidence is severely limited by lack of detail because only meeting abstracts and one associated slide presentation were available.  None of the studies cited has as yet been published in a peer-reviewed journal.  Based on the information available, it seems unlikely that the 12-gene expression test for predicting colon cancer recurrence risk in individual patients could guide clinical decision making because the differences between recurrence risk categories established in the validation study were not sufficiently discriminative and the associated CI overlapped considerably.  For example, a RS of 33 corresponds to a recurrence risk of 16%, which could be low-, intermediate-, or high-risk when CI of the category mean estimates are considered.  For interpretation, Genomic Health has established RS category ranges for low- (<30), intermediate- (30–40) and high- (>41) risk categories.  There is also no information from the validation study on how the test adds to current methods of predicting risk, and how extensively and accurately patients are reclassified by RS after classification by current predictors and compared to their known recurrence outcomes.

Summary

The only evidence currently available concerning  Oncotype DX Colon Cancer Assay consists of meeting abstracts and one associated slide presentation.  The results of one assay validation study (separate from assay development) suggest that the 12-gene expression test RS increases continuously with increasing risk of colon cancer recurrence, and that RS is independent of other standard clinical and pathological predictors of recurrence risk.  However, detailed information regarding the validation study and results is absent due to lack of a fully published, peer-reviewed report.  The limited results suggest insufficient discrimination between risk categories to direct post-surgery patient treatment.  Additional information available in other meeting presentation abstracts does not address risk category discrimination; nor does it address the extent and accuracy of reclassification by RS after classification by standard predictors.  Thus, a complete evaluation awaits full publication of the development and validation studies.

The evidence to date is insufficient to permit conclusions concerning the effect of the 12-gene expression test (Oncotype DX Colon Cancer Assay) on health outcomes.  Therefore, use of this test, including use to predict the likelihood of disease recurrence for patients with stage II colon cancer, is considered experimental, investigational and unproven.

Other Forms of Cancer:

The evidence to date is insufficient to permit conclusions concerning the utilization of gene expression testing for other forms of cancer on health outcomes.  Therefore, use of any gene expression testing, including use to predict the likelihood of disease recurrence for patients with any other form of cancer, is considered experimental, investigational and unproven.

Coding

Disclaimer for coding information on Medical Policies          

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.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

153.0, 153.1, 153.2, 153.3, 153.4, 153.5, 153.6, 153.7, 153.8, 153.9, 162.0, 162.2, 162.3, 162.4, 162.5, 162.8, 162.9, 174.0, 174.1, 174.2, 174.3, 174.4, 174.5, 174.6, 174.8, 174.9, 199.0, 199.1, 199.2, 230.3, 231.2, 233.0, 234.8, 234.9, 238.9, 239.9

Procedural Codes: 84999, 88299, S3854
References

Breast Cancer:

  1. Van Veer, L.J., Dai, H., et al.  Gene expression profiling predicts clinical outcomes in breast cancer.  Nature (2002 January 31) 415(6871):530-6.
  2. Van de Vijver, M.J., He Y.D., et al.  A gene-expression signature as a predictor of survival in breast cancer.  New England Journal of Medicine (2002 December 19) 347(25):1999-2009.
  3. Cobleigh, M.A., Bitterman, P., 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.  Proceedings of the American Society of Clinical Oncology – 2003 ASCO Annual Meeting (2003) 22:850 (abstract 3415).
  4. Esteban, J., Baker, J., et al.  Tumor gene expression and prognosis in breast cancer: multi-gene RT-PCR assay of paraffin-embedded tissue.  Proceedings of the American Society of Clinical Oncology – 2003 ASCO Annual Meeting (2003) 22:850 (abstract 3416).
  5. San Antonio Breast Cancer Symposium - Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients – National Surgical Adjuvant Breast and Bowel Project (NSABP) studies B-20 and B-14.  Prepared by Paik, S., Shak, S., et al. December 3-6, 2003 San Antonio Breast Cancer Symposium.  San Antonio, Texas.  (17 November 2004) http://www.abstracts2view .
  6. Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2004 March) Medicine 2.04.36.
  7. Ma, X.J., Wang, Z., et al.  A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen.  Cancer Cell (2004 June) 5(6):607-16.
  8. Paik, S., Shak, S., et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.  New England Journal of Medicine (2004 December 30) 351(27):2817-26.
  9. Taube, S.E., Jacobson, J.W., et al. Cancer diagnostics: decision criteria for marker utilization in the clinic.  American Journal of Pharmocogenomics (2005) 5(6):357-64.
  10. Gene Expression Profiling for Managing Breast Cancer Treatment.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2005 May) 20(3):1-31.
  11. Reid, J.F., Lusa, L., et al.  Limits of predictive models using microarray data for breast cancer clinical treatment outcome.  Journal of the National Cancer Institute (2005 June 15) 97(12):927-30.
  12. Gianni, L., Zambetti, M., et al.  Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.  Journal of Clinical Oncology (2005 October 10) 23(29):7265-77.
  13. Espinosa, E., Vara, J.A., et al.  Breast cancer prognosis determined by gene expression profiling: a quantitative reverse transcriptase polymerase chain reaction study.  Journal of Clinical Oncology (2005 October 10) 23(29):7278-85.
  14. Glas, A.M., Floore, A., et al.  Converting a breast cancer microarray signature into a high-throughput diagnostic test.  BMC Genomics (2006) 7:278.
  15. Habel, L.A., Shak, S., et al.  A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.  Breast Cancer Research (2006) 8(3):R25.
  16. Paik, S.  Methods for gene expression profiling in clinical trials of adjuvant breast cancer therapy.  Clinical Cancer Research (2006 February 1) 12(3 Part 2):1019s-23s.
  17. Goetz, M.P., Suman, V.J., 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.  Clinical Cancer Research (2006 April 1) 12(7 Part 1):2080-7.
  18. Dowsett, M., Houghten, J., et al.  Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according estrogen receptor, progesterone receptor, EGF receptor and HER2- status.  Annals of Oncology (2006 May) 17(5):818-26.
  19. Ring, B.Z., Seitz, R.S., et al.  Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer.  Journal of Clinical Oncology (2006 July 1) 24(19):3039-47.
  20. Paik, S., Tang, G., et al.  Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.  Journal of Clinical Oncology (2006 August 10) 24(23): 3726-34.
  21. Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2006 September) Medicine 2.04.36.
  22. Buyse, M., Loi, S., et al.  Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer.  Journal of the National Cancer Institute (2006 September 6) 98(17):1183-92.
  23. Ma, X.J., Hilsenbeck, S.G., et al.  The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer.  Journal of Clinical Oncology (2006 October 1) 24(28):4611-9.
  24. Jansen, M.P., Sieuwertz, A.M., et al.  HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: a retrospective study.  Journal of Clinical Oncology (2007 February 20) 25(6):662-8.
  25. Mina, L., Soule, S.E., et al.  Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue.  Breast Cancer Research and Treatment (2007 June) 103(2):197-208.
  26. Goldhirsch, A., Wood, W.C., et al.  Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007.  Annals of Oncology (2007 July) 18(7):1133-44.
  27. Gene Expression Profiling of Breast Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Bulletin (2007 September 26) 24(2):1-10.
  28. Harris, L., Fritsche, H., et al.  American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer.  Journal of Clinical Oncology (2007 November 20) 25(33):5287-312.
  29. Breast Cancer Update Summary – Practice Guidelines in Oncology (v.1.2008).  Pennsylvania, Fort Washington: National Comprehensive Cancer Network, Inc., Guidelines Index, Breast Cancer TOC Staging, MS, Research (2007 December 12):1-2.
  30. Jerevall, P.L., Brommesson, S., et al.  Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome.  Breast Cancer Research and Treatment (2008 January) 107(2):225-34.
  31. Breast Cancer – Practice Guidelines in Oncology (v.2.2008).  Pennsylvania, Fort Washington: National Comprehensive Cancer Network, Inc., Guidelines Index, Breast Cancer TOC Staging, MS, Research (2008 January 3):13-7.
  32. Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 January) Medicine 2.04.36.
  33. Gennari, A., Sormani, M.P., et al.  HER2- status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials.  Journal of the National Cancer Institute (2008 January 8) 100(1):14-20.
  34. Chang, J.C., Makris, A., et al.  Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients.  Breast Cancer Research and Treatment (2008 March) 108(2):233-40.
  35. Marchionni, L., Wilson, R.F., et al.  Systematic review: gene expression profiling assays in early-stage breast cancer.  Annals of Internal Medicine (2008 March 4) 148(5):358-69.
  36. Ma, X.J., Salunga, R., et al.  A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer.  Clinical Cancer Research (2008 May 1) 14(9):2601-8.
  37. Wittner, B.S., Sgroi, D.C., et al.  Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort.  Clinical Cancer Research (2008 May 15) 14(10):2988-93.
  38. Badve, S.S., Baehner, F.L., 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.  Journal of Clinical Oncology (2008 May 20) 26(15):2473-81.
  39. Asad, J., Jacobson, A.F., et al.  Does oncotype DX recurrence score affect the management of patients with early-stage breast cancer?  American Journal of Surgery (2008 October) 196(4):527-9.
  40. Mook, S., Schmidt, M.K., et al.  The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study.  Breast Cancer Research and Treatment (2009 July) 116(2):295-302.
  41. Goldhirsch, A., Ingle, J.N., et al.  Thresholds for therapies: highlights of the St. Gallen International Expert Consensus on the primary therapy of early breast cancer 2009.  Annals of Oncology (2009 August) 20(8):1319-29.
  42. Bueno-de-Mesquita, J.M., Linn, S.C., et al.  Validation of 70-gene prognosis signature in node-negative breast cancer.  Breast Cancer Research and Treatment (2009 October) 117(3):483-95.
  43. Ross, D.T., Kim, C.Y., et al.  Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials.  Clinical Cancer Research (2008 October 15) 14(20):6602-9.
  44. Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 November) Medicine 2.04.36.
  45. Straver, M.E., Glas, A.M., et al.  The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer.  Breast Cancer Research and Treatment (2010 February) 119(3):551-8.
  46. Turaga, K., Acs, G., et al.  Gene expression profiling in breast cancer.  Cancer Control (2010 July) 17(3):177-82.
  47. Roukos, D.H., Ziogas, D.E., et al.  Multigene assays and isolated tumor cells for early breast cancer treatment: time for bionetworks.  Expert Review of Anticancer Therapy (2010 August) 10(8):1187-95.

Colon Cancer:

  1. Kerr, D.J., Gray, R., et al.  Adjuvant chemotherapy with 5-fluorouracil, L-folinic acid and levamisole for patients with colorectal cancer: non-randomized comparison of weekly versus four-weekly schedules – less pain, same gain.  QUASAR Colorectal Cancer Study Group.  Annals of Oncology (2000 August) 11(8):947-55.
  2. Figueredo, A., Coombes, M.E., et al.  Adjuvant therapy for completely resected stage II colon cancer.  Cochrane Database Systematic Review (2008) (3):CD005390.
  3. Kerr, D.J., Gray, R., et al.  A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.  ASCO Meeting Abstracts (2009) 27:abstract 4000.
  4. O’Connell, M.J., Lavery, I.C., et al.  Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score.  ASCO Gastrointestinal Cancers Symposium (2010):abstract 280.
  5. Gray, R.G., Quirke, K., et al.  Correlation of number of nodes examined and the 12-gene colon cancer recurrence score with recurrence in stage II colon cancer patients from QUASAR.  ASCO Gastrointestinal Cancers Symposium (2010):abstract 331.
  6. Marshall, J.L.  Risk assessment in stage II colorectal cancer.  Oncology (Williston Park) (2010 January) 24(1 Supplement 1):9-13.
  7. Multigene Expression Assay for Predicting Recurrence in Colon Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2010 March) Medicine 2.04.61.
  8. Zamboni, B.A., Yothers, G., et al.  Conditional survival and the choice of conditioning set for patients with colon cancer: an analysis of NSABP trials C-03 through C-07.  Journal of Clinical Oncology (2010 May 20) 28(15):2544-8.
  9. O’Connell, M.J., Lavery I.C., et al.  Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin.  Journal of Clinical Oncology (2010 September 1) 28(25):3937-44.
  10. Genomic Health – Genomic Health Announces Worldwide Availability of the OncotypeDX® Colon Cancer Test Press Release.  Genomic Health (2010 January 21).  Available at http://genomichealth.com (accessed – 2010 September 20).
  11. National Comprehensive Cancer Network.  Clinical Practice Guidelines in Oncology.  Colon Cancer, V 1.2011.  Available at http://www.nccn.org (accessed 2010 September 20).

Other Forms of Cancer:

  1. Baker, J.  Genomic Health, Inc.  Pharmacogenomics (2007 April) 8(4):397-9.
  2. Subramanian, J., and R. Simon.  What should physicians look for in evaluating prognostic gene-expression signatures?  National Review of Clinical Oncology (2010 June) 7(6):327-34.
History
October 2011 Updated policy statement adding to medical necessity statment allowing with in 6 months following diagnosis. Updated rationale and references, no changes to coding
October 2013 Policy formatting and language revised.  Policy statement unchanged.  Title changed from "Breast Cancer - Assays of Genetic Expression to Determine Prognosis (e.g., MammaPrint®, Oncotype DX™)" to "Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Cancer".  Removed CPT codes 88360, 88361, 88367, 88368, and 89240.
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Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Cancer