Medical Policy: 02.04.28 

Original Effective Date: March 2010 

Reviewed: March 2021 

Revised: March 2021 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Gene expression profiling (GEP) assays have been developed for use as prognostic markers in stage II or stage III colon cancer to help identify those individuals who are at high risk for recurrent disease and could be candidates for adjuvant chemotherapy.

 

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2020, an estimated 104,610 new cases of colon cancer and 43,340 cases of rectal cancer will occur. During the same year, an estimated 53,200 people will die of colon and rectal cancer combined. (NCCN Version 2.2021)

 

The American Cancer Society estimates for the number of colorectal cancer cases in the United States for 2021 are:

  • 104,270 new cases of colon cancer
  • 45,230 new cases of rectal cancer

 

Stage II or III Colon Cancer

Clinical Context and Test Purpose

The purpose of prognostic testing of diagnosed disease is to predict natural disease course (e.g., aggressiveness, risk of recurrence, death). This type of testing uses gene expression of affected tissue to predict the course of the disease.

 

Patients

The relevant population of interest are patients who have undergone surgery for stage II or stage III colon cancer and are being evaluated for adjuvant chemotherapy.

 

Interventions

The interventions of interest are gene expression profiling (GEP) assays with Oncotype DX Colon Recurrence Score, ColoPrint 18-Gene Colon Cancer Recurrence Assay, GeneFx Colon (ColDx), and OncoDefender-CRC.

 

These tests are offered commercially through various manufacturers and would be performed on tumor tissue after surgical resection.

 

Comparator

The comparator of interest is standard of care without prognostic testing. The current standard of care is not to provide adjuvant chemotherapy to patients with stage II colon cancer and to administer adjuvant chemotherapy to patients with stage III colon cancer.

 

Outcomes

The outcomes of interest are recurrence risk, recurrence-free survival, and overall survival at follow-up in patients classified as low-risk, medium-risk, or high-risk by gene expression (GEP).

 

The time of interest is 3 to 5 years after surgical resection to assess colon cancer recurrence, given that the majority of colon cancer recurrences occur within the first 3 years after surgical resection of the primary tumor and approximately 95% in the first 5 years.  

 

In the treatment of colon cancer stage II, 75% to 80% are cured by surgery alone, and the absolute benefit of chemotherapy for the overall patient population is small. Patients most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathologic risk factors. Genomic tests are intended to facilitate identifying stage II patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.

 

Staging 

The tumor, node, metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) is the preferred staging system for colorectal cancer (CRC). 

 

In the 8th edition of the AJCC Staging Manual, T1 tumors involve the submucosa; T2 tumors penetrate through the submucosa into the muscularis propria; T3 tumors penetrate through the muscularis propria; T4a tumors directly penetrate to the surface of the visceral peritoneum; and T4b tumors directly invade or are adherent to other organs or structures. Regional lymph node classification includes N1a (1 positive lymph node); N1b (2-3 positive lymph nodes), N2a (4-9 positive lymph nodes); and N2b (7 or more positive lymph nodes). In addition, tumor deposit(s) in the subserosa mesentery, or non-peritonealized pericolic or perirectal tissues without regional nodal metastasis (i.e. satellite tumor nodules) have been classified as N1c. Metastatic disease is classified as M1a when metastases that are limited to only one site/solid organ (including to lymph nodes outside the primary tumor regional drainage area) are positive. M1b is used for metastases to multiple distant sites or solid organs, exclusive of peritoneal carcinomatosis. The 8th edit of the AJCC Cancer Staging Manual includes the M1c category for peritoneal carcinomatosis with or without blood-borne metastasis to visceral organs.

 

Stage II Colorectal Cancer
Stage TNM Description
IIA T3, N0, M0 T3 = Tumor invades through muscularis propria into pericolorectal tissues
N0 = No regional lymph node metastasis
MO = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
IIB T4a,N0, M0 T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum)
N0 = No regional lymph node metastasis
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
IIC T4b, N0, M0 T4b = Tumor directly invades or adheres to adjacent organs or structures
N0 = No regional lymph node metastasis
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs

 

The clinical and pathologic features used to identify high risk disease are not well established and patients for whom benefits of adjuvant chemotherapy would most likely outweigh harms cannot be identified with certainty. The current diagnostic system relies on a variety of factors, including tumor stage (tumors that invade the muscularis propria and extend into pericolorectal tissues; tumors that invade or are adherent to other organs or structures), obstruction or bowel perforation at initial diagnosis, an inadequately low number of sampled lymph nodes at surgery (< 12), histologic features of aggressiveness, an high preoperative carcinoembryonic antigen level, and indeterminate or positive resection margins.

 

Stage III Colorectal Cancer
Stage TNM Description
IIIA T1, N2a, M0
T1-2, N1/N1c, M0
T1 = Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria)
N2a = Four to six regional lymph nodes are positive
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
T1 = Tumor invades submucosa (through the muscularis mucosa but not into the muscularis propria)
T2 = Tumor invades the muscularis propria
N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring > 0.2 mm); or any number of tumor deposits are present and all identifiable lymph nodes are negative
N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
IIIB T1-T2, N2b, M0
T2-T3, N2a, M0
T3-T4a, N1/N1c, M0
T1 = Tumor invades submucosa (through the muscularis mucosa but not into the muscularis propria)
T2 = Tumor invades the muscularis propria
N2b = seven or more regional lymph nodes are positive
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
T2 = Tumor invades the muscularis propria
T3 = Tumor invades through the muscularis propria into pericolorectal tissues
N2a = Four to six regional lymph nodes are positive
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
T3 = Tumor invades through the muscularis propria into pericolorectal tissues
T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure
  • T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum)
N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring > 0.2 mm); or any number of tumor deposits are present and all identifiable lymph nodes are negative
N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
IIIC T3-T4a, N2b, M0
T4a, N2a, M0
T4b, N1-N2, M0
T3 = Tumor invades through the muscularis propria into pericolorectal tissues
T4 = Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure
  • T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum)
N2b = Seven or more regional lymph nodes are positive
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
T4a = Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum)
N2a = Four to six regional lymph nodes are positive
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs
T4b = Tumor directly invades or adheres to adjacent organs or structures
N1 = One to three regional lymph nodes are positive (tumor in lymph nodes measuring > 0.2 mm); or any number of tumor deposits are present and all identifiable lymph nodes are negative
  • N1a = One regional lymph node is positive
  • N1b = Two or three regional lymph nodes are positive
  • N1c = No regional lymph nodes are positive, but there are tumor deposits in the subserosa, mesentery, or nonperitonealized pericolic, or perirectal/mesorectal tissues
N2 = Four or more regional lymph nodes are positive
  • N2a = Four to six regional lymph nodes are positive
  • N2b = Seven or more regional lymph nodes are positive
M0 = No distant metastasis by imaging; no evidence of tumor in distant sites or organs

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

ColoPrint 18-Gene Colon Cancer Recurrence Assay

In 2015, Kepetz et. al. reported on a pooled analysis of 416 patients with stage II colon cancer from five different hospitals in Europe and one hospital in the United States. ColoPrint was compared with clinical risk factors described in the National Comprehensive Cancer Network (NCCN) 2013 Guidelines for Colon Cancer (T4; high grade tumor; lymphovascular or perineural invasion; perforation or obstruction; <12 lymph nodes examined; positive margins). Median follow-up was 81 months. Most patients (70%) did not receive adjuvant chemotherapy. Risk of relapse (ROR) was defined as survival until first event of recurrence or death from cancer. In the pooled stage II data set, ColoPrint identified 63% of patients as low risk with a 5-year ROR of 10%, whereas high-risk patients (37%) had a 5-year ROR of 21%, with a hazard ratio (HR) of 2.16 (p = .004). This remained significant in a multivariate model that included number of lymph nodes retrieved and microsatellite instability. In the T3 microsatellite-stable subgroup (n = 301), ColoPrint classified 59% of patients as low risk with a 5-year ROR of 9.9%. High-risk patients (31%) had a 22.4% ROR (HR: 2.41; p = .005). In contrast, the NCCN clinical high-risk factors were unable to distinguish high- and low-risk patients (15% vs. 13% ROR; p = .55). Thirty percent (30%) of patients received adjuvant 5-FU based chemotherapy. The decision to administer adjuvant chemotherapy as correlated with cohort site, year, and clinical risk factors but was not correlated with ColoPrint results, which were not available to the treating physicians. The outcome of patients was not improved by chemotherapy (p = 0.88). Patients who did not receive chemotherapy had a 5-year ROR of 13.8% (95% CI: 9.7% – 17.9%), whereas patients whor eceived therapy had a 5-year ROR of 14.8% (95% CI: 8.5% – 21.1%). Although there was no difference in the outcomes of patients treated or not treated with adjuvant therapy, conclusions are limited based on these findings because patients were not treated within a randomized clinical trial and the potential benefit of chemotherapy may be too small (3%–5%) to be detected in this limited data set.

 

GeneFx Colon (Also Known as ColDx)

Niedzwiecki et. al. (2016) reported on the association between results of a gene expression signature assay (ColDx also known as GeneFx Colon) and recurrence free interval in patients with stage II colon cancer in Cancer and Leukemia Group B 9581 as part of the Alliance phase III trial. C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI (recurrence free interval) adjusting for standard prognostic variables.
Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. In the subset of 271 patients for whom data are available from both assays (OncotypeDX and ColDx), there is low correlation between the continuous scores (R = 0.18). Although there is some overlap, it does not seem that the signatures are measuring the same thing or identifying the same patients at high risk. Further analysis is being conducted in this patient subset.

 

OncoDefender-CRC

Lenehan et. al. (2012) reported on the development and validation of a tumor derived 5-gene prognostic signature (OncoDefender-CRC) for recurrence of lymph node-negative invasive colorectal carcinoma (CRC). A total of 417 cancer-associated genes were preselected for the study of archived FFPE (formalin-fixed paraffin-embedded) primary adenocarcinoma tissues from 74 patients with CRC (15 with stage I disease and 59 with stage II disease). Patients were divided into a training set and a test set. In addition, FFPE tissues were retrieved from 49 patients with stage I CRC and 215 patients with stage II colon cancer for an External Validation (EV) Set (n = 264) from 18 hospitals in 4 countries. No patients had received neoadjuvant/adjuvant therapy. The test appeared to distinguish patients at high versus low risk or recurrence (HR = 1.63; p = 0.031). Sensitivity and specificity of OncoDefender-CRC were compared with NCCN guidelines and showed similar sensitivity (69% versus 73%) with improved specificity (48% versus 26%). However, the isolated performance of the test in patients with stage II colon cancer was not reported, and several NCCN high-risk findings (bowel obstruction or perforation and lymphovascular invasion) demonstrated higher HRs than observed with the molecular signature. The study alluded to but did not directly address clinical utility.

 

OncotypeDX Colon Recurrence Score

Reimers et. al. (2014) conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and III rectal cancer patients from the Dutch Total Mesorectal Excision (TME) trial. RNA was extracted from fixed paraffin-embedded primary rectal tumor tissue from stage II and III patients randomized to TME surgery alone, without (neo) adjuvant treatment. Recurrence Score was assessed by quantitative real time-polymerase chain reaction using previously validated colon cancer genes and algorithm. Data were analysed by Cox proportional hazards regression, adjusting for stage and resection margin status. All statistical tests were two-sided. Recurrence Score predicted risk of recurrence (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.11 to 2.21, P = .01), risk of distant recurrence (HR = 1.50, 95% CI = 1.04 to 2.17, P = .03), and rectal cancer-specific survival (HR = 1.64, 95% CI = 1.15 to 2.34, P = .007). The effect of Recurrence Score was most prominent in stage II patients and attenuated with more advanced stage (P(interaction) ≤ .007 for each endpoint). In stage II, five-year cumulative incidence of recurrence ranged from 11.1% in the predefined low Recurrence Score group (48.5% of patients) to 43.3% in the high Recurrence Score group (23.1% of patients). Risk classification with Recurrence Score and estimated recurrence risks for patients with stage III rectal cancer were not reported.

 

In 2016, Yamanaka et. al. evaluated the 12-gene Recurrence Score assay for stage II and III colon cancer without chemotherapy to reveal the natural course of recurrence risk in stage III disease in the SUNRISE Study. A cohort-sampling design was used. From 1,487 consecutive patients with stage II to III disease who had surgery alone, 630 patients were sampled for inclusion with a 1:2 ratio of recurrence and nonrecurrence. Sampling was stratified by stage (II versus III). The assay was performed on formalin-fixed, paraffin-embedded primary cancer tissue. Association of the Recurrence Score result with recurrence-free interval (RFI) was assessed by using weighted Cox proportional hazards regression. Overall, 597 of 630 patients were analyzable 247 patients had stage II, and 350 had stage III colon cancer. The continuous Recurrence Score was significantly associated with RFI after adjustment for disease stage (hazard ratio for a 25 unit increase in Recurrence Score, 2.05; 95% CI, 1.47 to 2.86; P < .001). With respect to prespecified subgroups, as defined by low (< 30), intermediate (30 to 40), and high (≥ 41) Recurrence Score risk groups, patients with stage II disease in the high-risk group had a 5-year risk of recurrence similar to patients with stage IIIA to IIIB disease in the low-risk group (19% versus 20%), whereas patients with stage IIIA to IIIB disease in the high-risk group had a recurrence risk similar to that of patients with stage IIIC disease in the low-risk group (approximately 38%).

 

Summary

Several validation studies of gene expression profiling (GEP) testing for colon cancer have reported that testing provides prognostic information on the risk of recurrence. Some studies have reported that GEP testing offers prognostic information in a multivariate analysis. Other data have suggested that GEP testing may provide modest incremental prognostic information over the standard prognostic work-up, including the NCCN risk prediction model. Patients with a low recurrence score have a lower risk of recurrence and patients with a high risk score have a higher risk of recurrence. However, the increase in recurrence risk for a high-risk score is small, and it is uncertain whether the degree of increase is sufficient to intensify management.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved in patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

 

A technical brief, published by the Agency for Healthcare Research and Quality in December 2012, reviewed the clinical evidence for gene expression profiling (GEP) assys for predicting outcomes, including benefit from adjuvant chemotherapy, in patients with stage II colon cancer. The 4 commercially available assays reviewed were included in the brief. No prospective studies were identified that assessed change in net health outcome with the use of a GEP assay, and no studies were identified that used a net reclassification analysis and subsequently evaluated the impact of reclassification on net health outcome. Additionally, evidence was limited on the reproducibility of test findings, indications for GEP testing in stage II patients, and whether results of GEP assays can stratify patients into groups with clinically meaningful differences in recurrence risk. No studies have been identified in subsequent literature updates that evaluated the impact of GEP testing on recurrence in patients with stage II or III colon cancer.

 

In the absence of direct evidence, an indirect chain of evidence could demonstrate clinical utility if all links in the chain are intact. An indirect chain of evidence for clinical utility of GEP testing involves the following series of questions:

  • Does GEP testing provide prognostic information? Yes. Patients with a low recurrence score have a decreased risk of recurrence and patients with a high-risk score have a higher risk of recurrence. However, the degree of difference in risk conferred by the test is not large.
  • Does GEP testing provide incremental prognostic information compared to the standard clinical workup for prognosis? Uncertain. No well-done studies have compared the prognostic information from GEP testing to standard prognostic information provided by clinical and pathologic workup.
  • Does the incremental prognostic information lead to classifying patients into different groups for which management differs? No. There are no well-defined treatment protocols that differ according to risk of recurrence. The intensity of surveillance and management may be impacted by results of GEP testing, but the evidence to demonstrate this is weak and not definitive.
  • Do the changes in management resulting from GEP testing lead to improvements in health outcomes? No. There is no evidence that different treatment protocols for patients with different risks of recurrence improve outcomes.

 

The findings of this technical brief state: Published studies have not provided information related to clinical utility, the effect that using the GEP result in patient care has on net health outcome. Limited information was found for analytic validity. The current evidence does not provide the type of information needed to answer major questions about use of GEP assays in these patients.

 

The technical brief concluded although information is emerging about the use of GEP assays to inform the decision about use of adjuvant chemotherapy in patients with stage II colon cancer, studies to date have not provided the type of information needed to address major uncertainties.

 

An evidence report conducted for the Washington State Health Care Authority (2017) reviewed the clinical utility of gene expression profile tests for cancer, including ColoPrint and Oncotype DX for stage II and III colon cancer. The researchers identified no clinical utility studies with mortality, morbidity, or harms outcomes.

 

Summary

Some studies have reported management changes following gene expression profiling (GEP) testing. However, these studies did not report clinical outcomes, and there is no direct evidence to determine whether GEP testing improves net health outcomes. A chain of evidence might be constructed if there was evidence that changes in the management for patients with stage II colon cancer improve health outcomes. The intensity of surveillance and management may be impacted by results of GEP testing, but the evidence to demonstrate that a change in management improve health outcomes is weak and not definitive. Therefore, the evidence does not demonstrate clinical utility.

 

Summary of Evidence

For individuals who have stage II or III colon cancer who receive gene expression profiling (GEP) testing, the evidence includes development and validation studies, and decision-impact studies. The available evidence has shown that gene expression profiling(GEP) testing for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with stage II or III colon cancer, however, the degree of difference in risk conferred by the test is small. Evidence to date does not permit conclusions on whether GEP classification is sufficient to modify treatment decisions in stage II or III colon cancer patients. Studies showing management changes as a consequence of testing have not demonstrated whether such changes improve outcomes. The current NCCN guideline Colon Cancer Version 2.2021 states the following: "The information from these tests can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, evidence of predictive value in terms of the potential benefit of chemotherapy is lacking. Therefore, the panel believes that there are insufficient data to recommend the use of multigene assays to estimate risk of recurrence or determine adjuvant therapy. The NCCN Panel encourages enrollment in clinical trials to help with the generation of additional data on these assays." The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory developed tests (LDTs) must meet the general regulatory standards of the Clinical Improvement Act (CLIA). Multigene expression assay testing for predicting recurrent colon cancer is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

 

Gene expression profiling tests for colon cancer currently commercially available include:

  • ColoPrint 18 - Gene Colon Cancer Recurrence Risk Assay (Agendia) – ColoPrint is a microarray-based 18 gene expression signature for predicting the risk of distant recurrence for stage II colon cancer who have undergone surgery.
  • GeneFx Colon (Helomics Therapeutics; also known as ColDx, Almac Diagnosistics) – Is a proprietary gene signature test (634 probe set signature) utilizing an individual patient’s RNA expression and a complex proprietary algorithm. GeneFx Colon is performed on a small amount of tumor tissue that categorizes patients as being at either high or low risk of having a tumor recurrence within 5 years of surgery. GeneFx Colon provides a clear result for risk recurrence that can help guide physicians regarding the use of adjuvant therapy in patients with colon cancer.
  • OncoDefender-CRC (Everist Genomics) – Is a prognostic gene-based laboratory assay (5 gene test) intended to help guide treatment decisions following tumor resection in patients with pathologically confirmed stage I or II colorectal cancer diagnosis. The OncoDefender-CRC assay evaluates the expression levels of a specific panel of genes from colorectal cancer tissue samples with a proprietary computation rule. The OncoDefender – CRC results report includes an indication of risk for cancer recurrence within 3 years of surgery (resection).
  • Oncotype DX Colon Recurrence Score (Genomic Health) – Oncotype DX Colon Cancer Assay uses an algorithm to generate a recurrence score result that is based on 12 genes: seven genes associated with recurrence and 5 genes used to normalize gene expression. This uses a technique called reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the expression of a panel of 12 genes in the tumor tissue. The recurrence score result is calculated from the gene expression results, and ranges from 0-100. This GEP assay is utilized in stage II patients with adenocarcinoma or mucinous carcinoma limited to the colon. It is unknown whether the findings apply to other patients outside this criteria.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Colon Cancer, Version 2.2021

Principles of Risk Assessment for Stage II Disease 
  • Patient/physician discussion regarding the potential risks of therapy compared to potential benefits, including prognosis. This should include discussion of evidence supporting treatment, assumptions of benefit from indirect evidence, morbidity associated with treatment, high-risk characteristics and patient preferences.
  • When determining if adjuvant therapy should be administered, the following should be taken into consideration:
    • Number of lymph nodes analyzed after surgery (<12)
    • Poor prognostic features (e.g., poorly differentiated histology [exclusive of those that are MSI-H]; lymphatic/vascular invasion; bowel obstruction; PNI; localized perforation; close, indeterminate, or positive margins)
    • Assessment of other comorbidities and anticipated life expectancy
  • The benefit of adjuvant chemotherapy does not improve survival by more than 5%
  • MSI or MMR testing

 

Decision making regarding the use of adjuvant therapy for patients with stage II disease should incorporate patient/physician discussions individualized for the patient and should include explanations of the specific characteristics of the disease and its prognosis and the evidence related to the efficacy and possible toxicities associated with treatment centering on patient choice. Observation and participation in a clinical trial are options that should be considered. Patients with average risk stage II colon cancer have a very good prognosis, so the possible benefit of adjuvant therapy is small. Patients with high-risk features on the other hand traditionally have been considered more likely to benefit from adjuvant chemotherapy. However, the current definition of high-risk stage II colon cancer is clearly inadequate, because many patients with high-risk features do not have a recurrence while some patients deemed to be average risk do. Furthermore, no data point to features that are predictive of benefit from adjuvant chemotherapy, and no data correlate risk features and selection of chemotherapy in patients with high-risk stage II disease. 

 

Overall, the NCCN Panel supports the conclusion of a 2004 ASCO Panel and believes that it is reasonable to accept the relative benefit of adjuvant therapy in stage III disease as indirect evidence of benefit for stage II disease, especially for those with high-risk features. Additional information that may influence adjuvant therapy decision for stage II and/or stage III disease (MSI, multigene assays, and the influence of patient age is discussed below. Research into additional possible predictive markers may allow for more informed decision-making in the future.

 

Multigene Assays

Several multigene assays have been developed in hopes of providing prognostic and predictive information to aid in decisions regarding adjuvant therapy in patients with stage II or III colon cancer.

  • Oncotype DX colon cancer assay quantifies the expression of 7 recurrence risk genes and 5 reference genes as prognostic classifier of low, intermediate or high likelihood of recurrence.
  • ColoPrint quantifies the expression of 18 genes as a prognostic classifier of low versus high recurrence risk.
  • ColDx is a microarray based multigene assay that uses 634 probes to identify patients with stage II colon cancer at high risk of recurrence.

 

In summary, the information from these tests can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, evidence of predictive value in terms of the potential benefit of chemotherapy is lackint. Therefore, the panel believes that there are insufficient data to recommend the use of multigene assay to estimate risk of recurrence or determine adjuvant therapy. ESMO has released similar recommendations regarding these assays, stating their role in predicting chemotherapy benefit is uncertain. The NCCN Panel encourages enrollment in clinical trials to help with the generation of additional data on these assays. 

 

Prior Approval:

Not applicable

 

Policy:

Gene expression profile (GEP) testing, including but not limited to the following, for the management of colon cancer is considered investigational for all indications, including but not limited to its use in estimating risk of disease recurrence or determining adjuvant therapy in individuals with stage II or III colon cancer following surgery:

  • Oncotype DX colon cancer assay
  • OncoDefender - CRC Assay
  • GeneFx colon (also known as ColDx)
  • ColoPrint

 

To date, the majority of the available studies fail to provide sufficient evidence that gene expression profiling (GEP) testing as a technique for colon cancer management leads to improved health outcomes. Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling (GEP) testing as a technique for colon cancer management compared with traditional clinical factors to guide medical management and improve clinical outcomes. The current NCCN guideline for Colon Cancer Version 2.2021 states: “the information from these tests can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, evidence of predictive value in terms of the potential benefit of chemotherapy is lacking. Therefore, the panel believes that there are insufficient data to recommend the use of multigene assay to estimate risk of recurrence or determine adjuvant therapy. ESMO has released similar recommendations regarding these assays, stating their role in predicting chemotherapy benefit is uncertain. The NCCN Panel encourages enrollment in clinical trials to help with the generation of additional data on these assays.” The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or Diagnosis codes.

  • 81525 Oncology (colon), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence score (OncotypeDX colon cancer assay)
  • 84999 Unlisted chemistry procedure (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); ColoPrint)
  • 88299 Unlisted cytogenetic study (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); ColoPrint)
  • 81599 Unlisted multianalyt assay with algorithmic analysis (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); ColoPrint)
  • 81479 Unlisted molecular pathology procedure (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); ColoPrint)

 

Selected References:

  • O'Connell MJ, Lavery I, Yothers G 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. J Clin Oncol 2010; 28(25):3937-44.
  • Gray RG, Quirke P, Handley K et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 2011; 29(35):4611-19.
  • Lenehan PF, Boardman LA, Riegert- Johnson D et al. Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma. Cancer. 2012 May 17. doi: 10.1002/cncr.27628. [Epub ahead of print].
  • Kennedy RD, Bylesjo M, Kerr P et al. Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol 2011; 29(35):4620-26.
  • Salazar R, Roepman P, Capella G et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 2011; 29(1):17-24.
  • Van Laar R. An online gene expression assay for determining adjuvant therapy eligibility in patients with stage 2 or 3 colon cancer. Br J Cancer 2010; 103(12):1852-7.
  • Hong Y, Downey T, Eu KW et al. A "metastasis-prone" signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis 2010;27(2):83-90.
  • Kelley RK, Van Bebber SL, Phillips KA et al. Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer. J Natl Compr Canc Netw. 2011;9(1):13-25.
  • Ross JS. Biomarker-based selection of therapy for colorectal cancer. Biomarkers in Medicine. 2011;5(3):319-32.
  • Webber EM, Lin JS, Evelyn PW. Oncotype DX tumor gene expression profiling in stage II colon cancer. Application: prognostic, risk prediction. PLoS Curr. 2010.
  • ECRI Multigene Expression Assay (Oncotype DX) for Predicting Recurrence of Colon Cancer. Plymouth Meeting (PA): ECRI Institute; 2011 Nov 16. [ECRI hotline response].
  • Maak M, Simon I et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surgery 2013 257(6)1053-8.
  • ECRI Institute. Oncotype DX multigene expression assay for predicting recurrence of colon cancer. ECRI Institute; 2013 Jul 2 [ECRI Procuct Brief]. Retrieved 7/11/13.
  • Validation Study of the 12-Gene Recurrence Score in Cancer and Leukemia Group B (CALGB) 9581. Journal of Clinical Oncology, Volume 31, Number 14, May 10, 2013. 
  • Screening for Colorectal Cancer:  U.S. Preventitive Services Task Force Recommendation Statement, Annals of Internal Medicine, Volume 149, Number 9, November 4, 2008.
  • National Comprehensive Cancer Network (NCCN) Colon Cancer, Version 2.2021.
  • ECRI Institute. Product Brief. Oncotype DX Multigene Expression Assay (Genomic Health, Inc) for Predicting Recurrence of Colon Cancer, June 2014.
  • UpToDate Adjuvant Chemotherapy for Resected Stage II Colon Cancer, Hanna K. Sanoff, M.D., MPH. Topic last updated July 11, 2019.
  • UpToDate Adjuvant Therapy for Resected Stage III (node-positive) Colon Cancer. Jeffrey W. Clark, M.D., Hanna K. Sanoff, M.D., MPH. Topic last updated January 15, 2019.
  • UpToDate Overview of Gene Expression Profiling, Proteomics and MicroRNA Profiling in Clinical Oncology, Patrick C ma, M.D., MSc. Topic last updated March 18, 2015.
  • Smith JJ, Deane NG, Wu F, et al. Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology. Mar 2010;138(3):958-968. PMID 19914252
  • Marisa L, de Reynies A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10(5):e1001453. PMID 23700391
  • Herrera M, Islam AB, Herrera A, et al. Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature. Clin Cancer Res. Nov 1 2013;19(21):5914-5926. PMID 24052018
  • Zhang JX, Song W, Chen ZH, et al. Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis. Lancet Oncol. Dec 2013;14(13):1295-1306. PMID 24239208
  • Maak M, Simon I, Nitsche U, et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg. Jun 2013;257(6):1053-1058. PMID 23295318
  • Kopetz S, Tabernero J, Rosenberg R, et al. Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist. Feb 2015;20(2):127-133. PMID 25561511
  • Lenehan PF, Boardman LA, Riegert-Johnson D, et al. Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma. Cancer. May 17 2012;118(21):5234-5244. PMID 22605513
  • Yothers G, O'Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. Dec 20 2013;31(36):4512-4519. PMID 24220557
  • Reimers MS, Kuppen PJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score as a predictor of recurrence risk in stage II and III rectal cancer patients. J Natl Cancer Inst. Nov 2014;106(11). PMID 25261968
  • Cartwright T, Chao C, Lee M, et al. Effect of the 12-gene colon cancer assay results on adjuvant treatment recommendations in patients with stage II colon cancer. Curr Med Res Opin. Feb 2014;30(2):321-328. PMID 24127781
  • Srivastava G, Renfro LA, Behrens RJ, et al. Prospective multicenter study of the impact of oncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer patients. Oncologist. May 2014;19(5):492-497. PMID 24710310
  • Black E, Falzon L, Aronson N. Gene Expression Profiling for Predicting Outcomes in Stage II Colon Cancer Technical Brief. No. 13. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-2007-0058-I.) Rockville, MD: Agency for Healthcare Research and Quality. December 2012. Accessed June 12, 2015.
  • Webber Elizabeth, Lin J, Whitlock E. Oncotype DX tumor gene expression profiling in stage II colon cancer. Application: Prognostic, risk prediction. Version 1 PLoS Curr 2010 September 2; 2 RRN1177.
  • ECRI Genetic Test Product Brief. Oncotype DX Multigene Expression Assay (Genomic Health, Inc.) for Predicting Recurrence of Colon Cancer. August 2015.
  • Reimers MS, Zeestraten EC,Kuppen PJ, et.al. Biomarkers in precision therapy in colorectal cancer. Gastroentrol Rep (Oxf) 2013 Nov:1(3):166-83
  • Goel G. Evolving role of gene expression signatures as biomarkers in early-stage colon cancer. J Gastrointest Cancer. 2014 Dec:45(4):399-404. PMID 24989938
  • Salazar R, Rosenberg R, Lutke Holzik M, et. al. The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint. [abstract]. J Clin Oncol. 2011;29(Suppl).
  • Vilar E, Gruber SB. Microsatellite instability in colorectal cancer the stable evidence. Nat Rev Clin Oncol. Mar 2010;7(3):153-162. PMID 20142816
  • Venook AP, Niedzwiecki D, Lopatin M, et. al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12 gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. May 10 2013;31(14):1775-1781. PMID 23530100
  • Breener B, Geva R, Rothney M, et. al. Impact of the 12-gene colon assay on clinical decision making for adjuvant therapy in stage II colon cancer patients. Value Health. Jan 2016;19(1):82-87. PMID 26797240 
  • UpToDate. Pathology and Prognostic Determinants of Colorectal Cancer. Carolyn C. Compton M.D., PhD. Topic last updated February 1, 2019.
  • OncoDefender-CRC.
  • GeneFX Colon.
  • ColoPrint.
  • Oncotype DX for Colon Cancer.
  • Niedzwiecki D, Frankel WL, Venook AP, et. al. Association between results of a gene expression signature assay and recurrence free interval in patients with stage II colon cancer in Cancer and Leukemia Group B 9581 (Alliance). J Clin Oncol. Sep 01 2016;34(25):3047-3053. PMID 27432924
  • Yamanaka T, Oki E, Yamazaki K, et. al. 12 gene recurrence score assay stratifies the recurrence risk in stage II/III colon cancer with surgery alone: The SUNRISE study. J Clin Oncol. Aug 20 2016;34(24):2906-2913. PMID 27325854
  • National Cancer Institute. Colorectal Cancer.

 

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  • March 2021 - Annual Review, Policy Revised
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