Medical Policy: 02.04.28 

Original Effective Date: March 2010 

Reviewed: March 2019 

Revised: March 2019 

 

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.

 

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.

 

Stage II Colorectal Cancer is divided into three subcategories: IIA, IIB and IIC. The difference between the categories lies in the extent to which the cancer has spread.

  • Stage IIA: The cancer has grown into the outermost layers of the colon or rectum, but has not grown through them. It has not reached nearby organs or lymph nodes, and has not spread to distant organs.
  • Stage IIB: The cancer has grown through all of the layers of the colon or rectum, but has not grown into other organs or tissues.
  • Stage IIC: The cancer has grown through all of the layers of the colon or rectum, and has grown into nearby organs or tissues. The cancer has not spread to the lymph nodes or distant organs.

 

For patients with stage III colon cancer that have spread to nearby lymph nodes, but they have not yet spread to other parts of the body, surgery to remove the section of the colon with the cancer along with nearby lymph nodes (partial colectomy) followed by adjuvant chemotherapy is the standard treatment for this stage.

 

Stage III Colorectal Cancer is further divided into three separate categories: IIIA, IIIB and IIIC. The difference between the categories lies in the extent to which the cancer has spread, and how many lymph nodes have been affected.

  • Stage IIIA: The cancer has grown into the submucosa. It may have also grown into the muscularis propria. The cancer has spread to 1-3 lymph nodes near the site of the primary tumor, but has not spread to distant sites.
  • Stage IIIB: The cancer has grown into the outermost layer of the colon or rectum, but has not reached nearby organs. Or, it has grown through the wall of the colon or rectum and into nearby organs or tissues. The cancer has spread to 1-3 lymph nodes near the primary site, but has not spread to distant organs.
  • Stage IIIC: The cancer may or may not have grown through the wall of the colon or rectum, but has spread to four or more lymph nodes near the primary site. The cancer has not metastasized to distant sites.

 

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 substage, 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 CEA level and indeterminate or positive resection margins.

 

In 2010 a review by Vilar and Gruber 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 disease-free survival who may derive no benefit or may exhibit deleterious effects from adjuvant 5-flurouracil plus leucovorin based treatments. The role of MSI as a genetic marker of Lynch Syndrome is well established in the clinical setting and is now the standard of care. Both MSI detection and immunohistochemistry are highly sensitive methods for the identification of individuals with a defective MMR system, and guide clinicians towards informative, cost effective genetic testing.

 

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.

 

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

 

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

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 routinely to patients with stage III colon cancer.

 

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

 

The time of interest is 5 to 10 years after surgical resection to assess colon cancer recurrence.

 

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

 

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. Fresh frozen tumor tissue from 188 patients with stage I to IV CRC undergoing surgery was analyzed using Agilent 44K oligonucleotide arrays. Median follow-up time was 65.1 months, and the majority of patients (83.6%) did not receive adjuvant chemotherapy. A nearest mean classifier was developed using a cross-validation procedure to score all genes for their association with 5-year distant metastasis-free survival. An optimal set of 18 genes was identified and used to construct a prognostic classifier (ColoPrint). The signature was validated on an independent set of 206 samples from patients with stage I, II, and III CRC. The signature classified 60% of patients as low risk and 40% as high risk. Five-year relapse-free survival rates were 87.6% (95% CI, 81.5% to 93.7%) and 67.2% (95% CI, 55.4% to 79.0%) for low- and high-risk patients, respectively, with a hazard ratio (HR) of 2.5 (95% CI, 1.33 to 4.73; P = .005). In multivariate analysis, the signature remained one of the most significant prognostic factors, with an HR of 2.69 (95% CI, 1.41 to 5.14; P = .003).

 

In a small independent validation study, Salazar et. al. (2011) used a patient cohort of 206 patients. However, only 56% (N=115) represented stage II tumors. Risk classification and survival for patient with stage II disease in this study includes the following: Follow-up 5 years; low risk 63.2%, mean RFS (risk free survival) for low risk 90.9%; high risk 36.8% and mean RFS (risk free survival) for high risk 73.9%

 

Maak et. al. (2013) conducted a study to independently validate the prognostic genomic signature (ColoPrint) for patients with stage II colon cancer to assist in treatment decisions. Previously, an 18-gene signature had been developed and validated on an independent cohort, using full genome microarrays. In this study, the gene signature was translated and validated as a robust diagnostic test (ColoPrint), using customized 8-pack arrays. In addition, clinical validation of the diagnostic ColoPrint assay was performed on 135 patients who underwent curative resection (R0) for colon cancer stage II in Munich. Fresh-frozen tissue, microsatellite instability status, clinical parameters, and follow-up data for all patients were available. The diagnostic ColoPrint readout was determined blindly from the clinical data. ColoPrint identified most stage II patients (73.3%) as at low risk. The 5-year distant-metastasis free survival was 94.9% for low-risk patients and 80.6% for high-risk patients. Information about net reclassification and clinical utility was not provided.

 

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)

In 2011, Kennedy et. al. reported on the development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded (FFPE) tissue. A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. The 634-probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001). The authors concluded, they plan further retrospective validation of the test in a large cohort of stage II colon cancer samples collected as part of a clinical trial.

 

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

In 2010, O’Connell et. al. conducted studies to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. They performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. The authors concluded, RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.

 

Gray et. al. (2011) sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy. Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95). The authors concluded, the continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS (treatment score) was not predictive of chemotherapy benefit.

 

In 2013, Venook et. al. conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. The authors concluded, the 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.

 

Yothers et. al. (2013) conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07. Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment. Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease.

 

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.

 

AssayValidated for Recurrence (Stage II)Validated for Treatment BenefitNet Reclassification AnalysisClinical Utility
ColoPrint Yes No For derivation study only No
ColonPRS Yes No No No
GeneFx Colon Yes No No No
OncoDefender-CRC No combined validation for stage I/II colon cancer No No No
OncotypeDX Colon Cancer Assay Yes No No No

 

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.

 

In 2014, Cartwright et. al. performed a retrospective study on the effect of the 12 gene colon cancer assay (OncotypeDX Colon Recurrence Score) on adjuvant treatment recommendations in patients with stage II colon cancer. U.S. medical oncologists (n = 346) who ordered the assay for ≥3 stage II colon cancer patients were asked to complete a web-based survey regarding their most recent such patient. Physicians surveyed represented users of the assay within the first 2 years of commercial availability which may include “early adopters”. Most of 116 eligible physicians were in community practice (86%), with median 14.5 years' experience (range = 2-40). Mean patient age was 61 years (range = 32-85); 81% had T3 disease, and 38% had comorbidities. Of 76 patients tested for mismatch-repair/microsatellite-instability (MMR/MSI), 13 (17%) were MMR-deficient/MSI-high; 46 (61%) MMR-proficient/MSI-low; and 17 (22%) unknown. Most patients (84%) had ≥12 nodes examined. Median Recurrence Score result was 20 (range = 1-77). Before assay, treatment recommendations were specified for 92 (79%) patients, with no recommendation for 24 (21%). Of the 92 with pre-assay recommendations, chemotherapy was planned for 52 (57%) and observation for 40 (43%); the assay changed recommendations for 27 (29%). Treatment intensity decreased for 18 (67%) and increased for nine (33%) patients; it was more likely to decrease for lower Recurrence Score values and increase for higher values (p < 0.001). The authors concluded, for stage II colon cancer patients receiving Recurrence Score testing, 29% of treatment recommendations were changed. Use of the assay may lead to reductions in treatment intensity. Study limitations include retrospective design, data gathering during the first 2 years of assay availability only, and potential non-representativeness of respondents.

 

In 2014, Srivastava et. al. performed a prospective multicenter study evaluating the impact of OncotypeDX colon cancer assay (recurrence score [RS]) on treatment recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%-53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). The authors concluded, compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

 

Brenner et. al. (2016) in a retrospective analysis evaluated the impact of the 12-gene colon cancer assay (OncotypeDX) on clinical decision making for adjuvant therapy in stage II colon cancer after surgical resection in T3 mismatch repair proficient (MMR-P) in stage II colon cancer clinical practice. This retrospective analysis included all patients with T3 MMR-P stage II colon cancer (Clalit Health Services members) with Recurrence Score results (time frame January 2011 to May 2012). Treatment recommendations pretesting were compared with the treatments received. Changes were categorized as decreased (to observation alone/removing oxaliplatin from the therapy) or increased (from observation alone/adding oxaliplatin to the therapy) intensity. The analysis included 269 patients; 58%, 32%, and 10% of the values were in the low (<30), intermediate (30-40), and high (≥41) score groups, respectively. In 102 patients (38%), treatment changed post-testing (decreased/increased intensity 76/26 patients). The overall impact was decreased chemotherapy use (45.0% to 27.9%; P < 0.001). Treatment changes occurred in all score groups, but more frequently in the high (change rate 63.0%; 95% confidence interval [CI] 42.3%-80.6%) than in the intermediate (30.6%; 95% CI 21.0%-41.5%) and low (37.6%; 95% CI 30.0%-45.7%) score groups. The direction of the change was consistent with the assay result, with increased intensity more common in higher score values and decreased intensity more common in lower score values. The authors concluded, testing significantly affected adjuvant treatment in T3 MMR-P stage II colon cancer in clinical practice. The study is limited by its design, which compared treatment recommendations pretesting to actual treatments received post-testing, lack of a control group, and non-assessment of confounding factors that may have affected treatment decisions.

 

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 do not demonstrate whether such changes improve outcomes. 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:

  • ColonPRS (Signal Genetics) – 163 gene expression assay for predicting risk of recurrence in individuals with colon cancer. No longer available.
  • 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. This process yields a relative measure of risk of recurrence within 3 years after surgery for stage I/II colon cancer patients.
  • 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 4.2018

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, assumption 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 taking 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 improve survival by more than 5%.
  • Microsatellite instability (MSI) or Mismatch Repair (MMR) Testing

 

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, there is no evidence of predictive value in terms of the potential benefit of chemotherapy to any of the available multigene assays. The panel believes that there are insufficient data to recommend the use of multigene assays to determine adjuvant therapy.

 

Prior Approval:

Not applicable

 

Policy:

Gene expression profile (GEP) testing, including but not limited to the following, as a technique for managing colon cancer is considered investigational for all indications, including but not limited to its use for predicting the likelihood of disease recurrence in individuals with 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 (i.e., clinical utility). 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 NCCN guidelines for colon cancer version 4.2018 states, “there is no evidence of predictive value in terms of the potential benefit of chemotherapy to any of the available multigene assays. The panel believes that there are insufficient data to recommend the use of multigene assays to determine adjuvant therapy”. 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 4.2018.
  • 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 November 28, 2018.
  • 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.

 

Policy History:

  • March 2019 - Annual Review, Policy Revised
  • March 2018 - Annual Review, Policy Revised
  • March 2017 - Annual Review, Policy Revised
  • March 2016 - Annual Review, Policy Revised
  • April 2015 - Annual Review, Policy Revised
  • October 2014 - Interim review, Policy Revise
  • May 2014 - Annual Review, Policy Revised
  • July 2013 - Annual Review, Policy Renewed
  • August 2012 - Annual Review, Policy Revised
  • August 2011 - Annual Review, Policy Renewed

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.