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Multigene Expression Assay for Predicting Recurrence in Colon Cancer

Policy Number: MP-587

Latest Review Date: August 2019

Category: Laboratory

Policy Grade: C

DESCRIPTION OF PROCEDURE OR SERVICE:

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

Colon Cancer

According to estimates by the National Cancer Institute, in 2019 over 145,000 new cases of colorectal cancer will be diagnoses in the United States, and over 51,000 people will die of this cancer. Five-year survival estimates are around 65%.

Colorectal cancer is classified as Stage II (also called Dukes B) when it has spread outside the colon and/or rectum to nearby tissue but is not detectable in lymph nodes (Stage III disease, also called Dukes C) and has not metastasized to distant sites (Stage IV disease). Primary treatment is surgical resection of the primary cancer and colonic anastomosis. After surgery prognosis is good, with survival rates of 75% to 80% at five years. A 2008 meta-analysis of 50 studies of adjuvant therapy versus surgery alone in Stage II patients found statistically significant, though small, absolute benefit of chemotherapy for disease-free survival (DFS) but not for overall survival. Therefore, adjuvant chemotherapy with 5-fluorouracil or capecitabine is recommended only for resected patients with high-risk Stage II disease (i.e., those with poor prognostic features).

Of patients with Stage II colon cancer, 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.

However, 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 system relies on a variety of factors, including tumor substage IIB (T4A tumors that invade the muscularis propria and extend into pericolorectal tissues) or IIC (T4B 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, a high preoperative carcinoembryonic antigen level, and indeterminate or positive resection margins.

Of interest, a review by Vilar and Gruber (2010) has noted that microsatellite instability (MSI) and mismatch repair (MMR) deficiency in colon cancer may represent confounding factors to be considered in treatment. These factors may identify a minority (15%-20%) of the population with improved DFS who may derive no benefit or may exhibit deleterious effects from adjuvant fluorouracil plus leucovorin-based treatments. Patient MSI and MMR status may be critically important in how to study, interpret, and use a particular GEP test.

POLICY:

Gene expression assays for determining the prognosis of colon cancer is considered not medically necessary and investigational for the following situations, including but not limited to:

  • Predicting the likelihood of disease recurrence for patients with Stage II colon cancer following surgery,
  • Predicting the likelihood of disease recurrence for patients with Stage III colon cancer following surgery.

KEY POINTS:

The most recent literature update was performed through June 13, 2019.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

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 disease.

The question addressed in this evidence review is: Does prognostic testing using the gene expression profiling (GEP) tests described below in individuals diagnosed with Stage II or Stage III colon cancer improve the net health outcome?

The specific clinical context of each test is described briefly in the following section. The following PICO elements were used to select literature to inform this review.

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 is gene expression profiling (GEP) with the ColoPrint 18-Gene Colon Cancer Recurrence Assay, GeneFx Colon (ColDx), OncoDefender-CRC, and Oncotype DX Colon Recurrence Score.

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 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 routinely 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 GEP.

The time of interest is five to ten years after surgical resection to assess colon cancer recurrence.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

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

Salazar et al (2011) described the development of an 18-gene expression test called the ColoPrint 18- Gene Colon Cancer Recurrence Assay. A total of 188 samples were prospectively collected from patients with colorectal cancer (CRC). RNA was isolated from fresh tissue frozen in liquid nitrogen, labeled and hybridized to customized whole-genome oligonucleotide high-density microarrays. A cross-validation procedure was performed on 33,834 gene probes that showed variation across the training samples. They were scored for their association with five year distant metastasis-free survival. From this pool of genes, an optimal set of 18 nonredundant probes was identified and used to construct classification scores for the test. Results were dichotomized into a two category, low- and high-risk, scoring system.

In a small independent validation study by Salazar et al (2011) used a patient cohort of 206 patients, however, only 56% represented Stage II tumors. Risk classification and survival are shown in Table 1 for the patients with Stage II disease in this study.

Maak et al (2013) conducted a subsequent validation study in fresh frozen tumor samples from patients who had undergone curative resection for Stage II colon cancer. Mismatch repair (MMR) status, clinical parameters, and follow-up data (median, 8.4 years) were collected. Five-year distant metastasis-free survival for patients classified as low risk and high risk are shown in Table 1. Information about net reclassification and clinical utility was not provided.

Table 1. RFS in Patients With Stage II Colon Cancer Assessed With ColoPrint

Author (Year)

Follow-Up, y

N

Low Risk, %

Mean RFS for Low Risk, %

High Risk, %

Mean RFS for High Risk, %

Salazar et al (2011)

5

115

63.2

90.9

36.8

73.9

Maak et al (2013)

8.4a

135

95

80

RFS: recurrence-free survival. aMedian

In 2015, Kopetz et al reported a pooled analysis of 416 patients with Stage II colon cancer from independent cohorts in the United States, Spain, Italy, Austria, and Germany. Investigators compared the prognostic ability of ColoPrint® with National Comprehensive Cancer Network (NCCN) risk prediction based on clinicopathologic factors (T4; high-grade tumor; lymphovascular or perineural invasion; perforation or obstruction; <12 lymph nodes examined; and positive margins). Recurrence risk at a mean 81 months (range, 56-178 months) is shown in Table 2. Statistical comparison of the risk models (e.g., using a likelihood ratio test and/or receiver operating characteristic [ROC] curves) and comparison of classifications by survival outcomes (i.e., reclassification analysis) were not provided. Further, a five year recurrence risk as high as 14% in patients classified as low risk by ColoPrint® may be too high for some patients to consider foregoing chemotherapy.

Table 2. ColoPrint and NCCN Risk Prediction and RR in Patients With Stage II Colon Cancer

Author (Year)

Risk Prediction

Low Risk, n (%)

Mean RR for Low Risk (95% CI)

High Risk, n (%)

Mean RR for High Risk (95% CI)

Kopetz et al (2015)

ColoPrint

263 (63)

10 (7 to 14)

153 (37)

21 (14 to 28)

NCCN

236 (57)

13 (9 to 18)

180 (43)

15 (10 to 20)

CI: confidence interval; NCCN: National Comprehensive Cancer Network; RR: recurrence risk.

GeneFx Colon

Kennedy et al (2011) reported on the development of a 634-probe set signature. A training set of 215 patients (143 low risk, 73 high risk) was identified based on five year disease free survival (DFS). The assay was performed using a DNA-microarray analysis of formalin-fixed paraffin-embedded (FFPE) samples. Cross-validation studies were used to select an optimal transcript signature for prognostic classification. Independent validation was performed on 144 patients enriched for recurrence (85 low risk, 59 high risk) using the threshold score identified in the training set. The signature in this convenience sample of patients predicted disease recurrence with a hazard ratio (HR) of 2.53 (p<0.001) in the high-risk group. The signature also predicted cancer-related death with an HR of 2.21 (p<0.001) in the high-risk group.

In 2016, Niedzwiecki et al reported recurrence free interval from 393 patients out of 1738 treated in the Cancer and Leukemia Group B 9581 (CALGB 9581) trial. Treatment in CALGB 9581 was with an experimental monoclonal antibody (edrecolomab) or observation; there was no significant survival benefit of the experimental treatment. Of 901 eligible patients with available tissue, a randomized sample of 514 patients was selected. Final analysis included 360 patients in the randomized cohort (58 events) and 33 nonrandomly selected events that had samples that were successfully analyzed. The investigators hypothesized that the high failure rate was due to the long interval between sample collection and analysis (mean, 13.2 years). Recurrence scores in patients categorized as low risk and high risk are shown in Table 3. After adjustment for prognostic variables that included mismatch repair deficiency, patients categorized as high risk by GeneFx had significantly worse regression-free interval in unadjusted analysis (HR=2.13; 95% CI, 1.3 to 3.5; p<0.01). However, in multivariate analysis the GeneFx risk score was marginally associated with overall survival (HR=1.74; 95% CI, 0.97 to 3.1; p=0.06). For the 271 samples analyzed by both GeneFx and Oncotype DX (see below), there was little correlation in continuous scores (R=0.18).

Table 3. RFS in Patients With Stage II Colon Cancer Assessed With GeneFx

Author (Year)

Follow-Up, y

N

Low Risk, n (%)

Mean RFS for Low Risk (95% CI)

High Risk, n (%)

Mean RFS for High Risk (95% CI)

Niedzwecki et al (2016)

5

393

177 (45)

91 (89 to 93)

216 (55)

82 (79 to 85)

CI: confidence interval; RFS: recurrence-free survival.

OncoDefender-CRC

Lenehan et al (2012) reported on their development of a five gene test, OncoDefender®. A total of 417 cancer-associated genes were preselected for study in archived formalin-fixed, paraffin-embedded primary adenocarcinoma tissues of 74 patients with colorectal cancer (15 with Stage I disease, 59 with Stage II disease; 60 with colon cancer, 14 with rectal cancer). Patients were divided into a training set and a test set. Cross-validation was performed to estimate the ability of the classifier to generalize to unseen samples. The most important feature of gene fitness was the area under the ROC curve for each gene.

In addition, Lenehan et al (2012) performed external validation on 251 patients with Stage I and II colon cancer obtained from an international study set. Patient dropout from the set of archived samples used was substantial; only 264 (55%) of 484 patients with lymph node‒negative colorectal carcinoma satisfied the initial clinicopathologic screening. This included a mix of patients with both rectal and colon cancer (Stages I and II). The test appeared to distinguish patients at high versus low risk of recurrence with an HR of 1.63 (p=0.031). Sensitivity and specificity of OncoDefender® was compared with NCCN guidelines and showed similar sensitivity (69% vs 73%) with improved specificity (48% vs 26%). However, isolated performance of the test in patients with Stage II colon cancer was not reported, and several NCCN high-risk findings (bowel obstruction/perforation and lymphovascular invasion) demonstrated higher HRs than observed with the molecular signature. The study alluded to but did not directly address clinical utility.

Oncotype DX Colon Recurrence Score

O’Connell et al (2010) described the development of a 12-gene expression test, Oncotype DX® Colon Recurrence Score. 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 clinical outcomes in 1851 patients who had surgery with or without adjuvant 5-FU-based chemotherapy. Gene expression was quantified from microdissected, fixed paraffin-embedded primary colon cancer tissue. Of 761 candidate genes, multivariate analysis, including disease severity, stage, and nodal involvement, reduced the gene set to a seven gene prognostic signature and a separate six gene predictive signature. Five reference genes also are included in the assay.

There have been several validation studies. These are summarized in Tables 4 and 5. External validation of the algorithm was reported by Gray et al in 2011, who used FFPE primary tumor samples from patients with Stage II colon cancer who had participated in the Quick and Simple and Reliable (QUASAR) study. The relation between the seven gene recurrence score and risk of recurrence was statistically significant, with three year risk of recurrence for predefined low-, intermediate-, and high-risk groups as shown in Table 4. In the surgery alone group, the hazard ratio for recurrence in the high-risk group compared with the low-risk group was 1.47 (95% CI, 1.01 to 2.14, p=0.046).

Table 4. Oncotype DX Colon Validation Study Characteristics

Randomized Treatments

Colon Cancer, n

Study

Trial

Design

N

Intervention

Comparator

Stage II

Stage III

Gray et al (2011)

QUASAR

RCT

3239

Adjuvant chemotherapy

Surgery alone

1436

Venook et al (2013)

CALGB 9581

RCT

1713

Edrecolomab

Observation

690

Yothers et al (2013)

NASBP

C-07 R

RCT

2409

FULV with oxaliplatin

FULV without oxaliplatin

264

Reimers et al (2014)

TME

RCT

1861

Radiotherapy

No radiotherapy

130a

167a

Yamanaka et al (2016)

SUNRISE

Cohort

1487

Not applicable

247

350

CALGB 9581: Cancer and Leukemia Group B 9581 trial; FULV: 5-fluorouracil plus leucovorin; NASBP C-07: National Surgical Adjuvant Breast and Bowel Project; QUASAR: Quick and Simple and Reliable; RCT: randomized controlled trial; TME: Dutch total mesenteric excision (TME) trial. ᵅ Rectal.

In 2013, Venook et al reported a validation study using tumor tissue from patients with Stage II colon cancer who had participated in the randomized Cancer and Leukemia Group B (CALGB) 9581 trial. The investigators selected samples stratified by treatment group from those who had tumor tissue available (40% of the original patient sample). They used recurrence score cut points of 29 and 39 to determine low-, intermediate-, and high-risk groups (Table 4); these values differ from the cut points of 30 and 41 validated in the QUASAR study previously described. In multivariate analysis, every 25-unit change in recurrence score was associated with recurrence independent of tumor stage, tumor grade, MMR status, presence or absence of lymphovascular invasion, and number of nodes assessed.

Yothers et al (2013) conducted a validation study using tumor tissue from 264 patients with Stage II colon cancer who had participated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial. NSABP C-07 randomized 2409 patients with Stage II (28%) or Stage III (72%) colon cancer to adjuvant chemotherapy with 5-FU plus leucovorin (FULV) or oxaliplatin plus FULV (FLOX). For the randomly selected sample of 50% of patients with Stage II colon cancer, estimated five-year recurrence risks (adjusted for treatment) are shown in Table 5. Five-year recurrence risk, estimated by Kaplan-Meier analysis, was reduced in high-risk patients who received oxaliplatin 9% [95% CI, 3% to 25%] compared with those who did not 23% [95% CI, 12% to 42%, but this difference was not observed in low- or intermediate-risk patients. However, confidence intervals for these estimates were wide due to small numbers of patients and events in each risk group. For all Stage III patients in any risk class, adjusted five-year recurrence risk estimates exceeded 15%.

Table 5. Recurrence Rates With 3-Level Oncotype DX Colon Cancer Recurrence Risk Score

Mean Recurrence Rate (95% CI), %

Study

Trial

Risk Prediction, y

Low Risk

Medium Risk

High Risk

Gray et al (2011)

QUASAR

3

12

18

22

Venook et al (2013)

CALGB 9581

5

12 (10 to 15)

15 (12 to 17)

18 (14 to 22)

Yothers et al (2013)

NASBP C-07

5

9 (6 to 13)

13 (8 to 17)

18 (12 to 25)

Reimers et al (2014)

TME Stage II Cohort (rectal)

5

11 (6 to 22)

27 (16 to 46)

43 (29 to 65)

Yamanaka et al (2016)

SUNRISE Stage II Cohort

5

9 (7 to 12)

14 (11 to 17)

19 (13 to 24)

SUNRISE Stage III Cohort

5

20 (14 to 25)

29 (23 to 35)

38 (29 to 47)

CALGB 9581: Cancer and Leukemia Group B 9581 trial; CI: confidence interval; NASBP C-07: National Surgical Adjuvant Breast and Bowel Project; QUASAR: Quick and Simple and Reliable; TME: Dutch total mesenteric excision (TME) trial.

Reimers et al (2014) conducted a retrospective study using prospectively collected tumor specimens from the Dutch total mesenteric excision (TME) trial in patients with resectable rectal cancer. Reimers used available tumor tissue from 569 Stage II and Stage III patients randomized to surgery alone. Among 130 patients with Stage II rectal cancer, Oncotype DX classified 63 (49%) patients as low risk, 37 (28%) patients as intermediate risk, and 30 (23%) patients as high risk. Five-year Kaplan-Meier recurrence risk estimates in the low-, intermediate-, and high-risk groups are shown in Table 5. Oncotype DX risk classification and estimated recurrence risks for patients with Stage III rectal cancer were not reported.

The SUNRISE study (Yamanaka et al, 2016) evaluated tissue samples from consecutive patients with Stage II and Stage III colon cancer who had been treated with surgery alone. This was the standard of care at hospitals in Japan during the study period 2000 to 2005. From the total cohort of 1487 patients, samples were randomly selected from patients who had or did not have a recurrence, in a 1:2 ratio. The final number of patients studied was 597; 202 patients had disease recurrence and 395 had no recurrence. As shown in Table 5, the risk of recurrence in patients with Stage III colon cancer with a low--risk score was similar to patients with Stage II disease and a high-risk score, and exceeded 15%. When adjusted for disease stage, a 25-unit increase in the recurrence score had an HR of 2.05 (95% CI, 1.47 to 2.86; p<0.001).

Section Summary: Clinically Valid

Several validation studies of GEP 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 suggest 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 if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

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 by Black et al (2012), conducted for the Agency for Healthcare Research and Quality, reviewed the clinical evidence for GEP in predicting outcomes, including benefit from adjuvant chemotherapy, in patients with Stage II colon cancer. The four commercially available assays reviewed herein 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 the 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.

A more recent 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 or III colon cancer. The researchers identified no clinical utility studies with mortality, morbidity, or harms outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. A chain of evidence may be developed, which addresses two key questions.

  1. Does the use of GEP testing of colon cancer risk in individuals with Stage II or Stage III colon cancer lead to a change in management regarding the use of adjuvant chemotherapy?
  2. Do those management changes improve health outcomes?

Several studies have documented changes in management following GEP testing for colon cancer. For example, in 2016, Brenner et al published a retrospective study of the association between Oncotype DX recurrence score and management decisions. There were 269 patients from a health plan included who had Stage II colon cancer, MMR proficient status, and Oncotype DX recurrence scores. The primary outcome measures were changes in management that occurred following Oncotype DX testing. Patients were classified as having either an increase in the intensity of surveillance/treatment, a decrease in the intensity of surveillance/treatment, or no change. A change in management following testing was found for 102 (38%) of 269 patients. Of the 102 patients with management changes, there were 76 patients in whom the intensity of management was decreased and 26 in whom it was increased. More patients who had a low recurrence score had a decrease in intensity of management, and more patients with a high recurrence score had an increase in intensity.

Cartwright et al (2014) and Srivastava et al (2014) have also published studies showing the effect of Oncotype DX® results on treatment recommendations made according to traditional risk classifiers in patients with Stage II colon cancer. Cartwright et al (2014) performed a retrospective study predicting that test results may lead to reductions in treatment intensity in a percentage of patients. Srivastava et al (2014) performed a prospective study that directly demonstrated reductions in treatment intensity in a percentage of patients.

This type of study does not determine whether patient outcomes are improved as a consequence of the changes in management, and there are no well-defined treatment protocols that differ according to risk of recurrence within Stage II or within Stage III colon cancer.

Section Summary: Clinically Useful

Some studies have reported management changes following GEP testing. However, these studies do not report clinical outcomes and there is no direct evidence to determine whether GEP testing improves health outcomes. A chain of evidence might be constructed if there was evidence that changes in management for patients with Stage II colon cancer improved 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 leads to an improvement in 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 GEP testing, the evidence includes development and validation studies and decision-impact studies. The relevant outcomes are disease-specific survival, test accuracy and validity, and change in disease status. The available evidence has shown that 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 is insufficient to permit conclusions on whether GEP classification is sufficient to modify treatment decisions in Stage II or III patients. Studies showing management changes as a consequence of testing do not demonstrate whether such changes improve outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

Current clinical practice guidelines from the National Comprehensive Cancer Network (v.2.2019) on colon cancer state that “there is insufficient data to recommend the use of multigene assays to determine adjuvant therapy” in patients with Stage II or III colon cancer.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Colon cancer, colorectal cancer, OncotypeDX colon cancer, ColoPrint®, GeneFx colon®, OncoDefender®, gene expression profiling, Oncotype test, Oncotype DX®, Genomic Health, genetic testing, genetic test, gene expression assays

APPROVED BY GOVERNING BODIES:

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 this test.

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

  • ColoPrint® 18-Gene Colon Cancer Recurrence Assay (Agendia)
  • GeneFx™ Colon (Helomics Therapeutics; also known as ColDx, Almac Diagnostics)
  • OncoDefender-CRC™ (Everist Genomics)
  • Oncotype DX® Colon Recurrence Score (Genomic Health).

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT 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

81599

Unlisted multianalyte assay with algorithmic analysis

84999

Unlisted chemistry procedure

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  23. 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. Sep 1 2010; 28(25):3937-3944.
  24. 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).
  25. 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. Jan 1 2011;29(1):17-24.
  26. 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. J Clin Oncol 29: 2011 (suppl; abstr TPS167). //meetinglibrary.asco.org/content/81592-102.
  27. Salazar R, Tabernero J, Moreno V et al. Validation of a genomic classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of stage II colon cancer patients. J Clin Oncol 30: 2012 (suppl; abstr 3510). //meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/3510. Accessed June 12, 2015.
  28. 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.
  29. 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.
  30. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. Jun 2011; 12(6):575-582.
  31. Van Laar RK. An online gene expression assay for determining adjuvant therapy eligibility in patients with stage 2 or 3 colon cancer. Br J Cancer. Dec 7 2010; 103(12):1852-1857.
  32. 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.
  33. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. Mar 2010; 7(3):153-162.
  34. Wan YW, Qian Y, Rathnagiriswaran S, et al. A breast cancer prognostic signature predicts clinical outcomes in multiple tumor types. Oncol Rep. Aug 2010; 24(2):489-494.
  35. Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol. May 1 2004; 22(9):1564-1571.
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  37. 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.
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POLICY HISTORY:

Medical Policy Panel, March 2010

Medical Policy Group, April 2010 (1) Oncotype DX for colon cancer considered investigational

Medical Policy Administration Committee, April 2010

Medical Policy Group, April 2011 (1): Updated Key Points, Key Words, Coding and References for Oncotype DX® for colon cancer

Medical Policy Administration Committee, May 2011

Medical Policy Group, August 2011 (1): Update to Key Points and References for Oncotype DX for colon cancer, no change in policy statement

Medical Policy Panel, August 2012

Medical Policy Group, August 2012 (1) Update to Key Points and References; no change to policy statement

Medical Policy Panel, August 2013

Medical Policy Group, August 2013 (1) Update to Key Points and References; no change to policy statement

Medical Policy Panel, August 2014

Medical Policy Panel, August 2015

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added new CPT code 81525 to current coding section.

Medical Policy Group, January 2016 (3): Creation of individual policy with all coding and references related to OncotypeDX for colon cancer removed from medical policy #133. All sections updated; policy statement updated to Gene expression assays (rather than just Oncotype DX) and stage III colon cancer is investigational.

Medical Policy Administration Committee, February 2016

Medical Policy Panel, August 2016

Medical Policy Group, August 2016 (3): 2016 Update to Key Points and References; no change in policy statement

Medical Policy Panel, August 2017

Medical Policy Group, August 2017 (3): 2017 Updates to Description, Key Points, Key Words, Approved by Governing Bodies & References. No change in policy statement.

Medical Policy Panel, August 2018

Medical Policy Group, August 2018 (9): 2018 Updates to Description, Key Points. No change to policy statement.

Medical Policy Panel, August 2019

Medical Policy Group, August 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.