Coverage Policy Manual
Policy #: 2010015
Category: Laboratory
Initiated: August 2017
Last Review: August 2023
  Genetic Test: Colon Cancer, Gene Expression Profiling (Oncotype DX, Colon PRS, Onco Defender-CRC, ColoPrint)

Description:
Gene expression profile (GEP) and circulating tumor DNA (ctDNA) tests have been developed for use as prognostic markers of stage II or III colon cancer to help identify patients who are at high risk for recurrent disease and would be good candidates for adjuvant chemotherapy.
  
According to estimates by the National Cancer Institute, in 2022 over 151,000 new cases of colorectal cancer will be diagnosed in the U.S., and nearly 53,000 people will die of this cancer (NCI, 2022). Five-year survival estimates are around 65%. Disparities in colorectal cancer outcomes have been identified in different subgroup classifications based on race and ethnicity, age, socioeconomic status, insurance access, geography, and environmental exposures. For example, in the U.S. between 2012- 2016, mortality rates were highest amongst non-Hispanic Black patients (incidence rate of 45.7 per 100,000), which were 20% and 50% higher than rates amongst non-Hispanic White and Asian patients, respectively. Additionally, non-Hispanic Black patients may have limited opportunities for therapeutic interventions due to experiencing higher inequities in comorbidities (Musselwhite, 2021).
 
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 the lymph nodes (stage III disease, also called Dukes C) and has not metastasized to distant sites (stage IV disease). The primary treatment is surgical resection of the primary cancer and colonic anastomosis. After surgery, the prognosis is good, with survival rates of 75% to 80% at 5 years (Figueredo, 2008). A Cochrane review by Figueredo et al, assessing 50 studies of adjuvant therapy versus surgery alone in stage II patients found a small though statistically significant absolute benefit of chemotherapy for disease-free survival but not for overall survival (Figueredo, 2008). Therefore, adjuvant chemotherapy with 5-fluorouracil (5-FU), capecitabine, CAPEOX (capecitabine and oxaliplatin), or FOLFOX (5-FU and oxaliplatin) is recommended only for resected patients with high-risk stage II disease (i.e. those. with poor prognostic features) (NCCN, 2022).
 
However, the clinical and pathological features used to identify high-risk disease are not well-established and patients for whom the benefits of adjuvant chemotherapy would most likely outweigh the harms cannot be identified with certainty. The current diagnostic system relies on the use of a variety of factors including tumor sub-stage IIB (T4a tumors that invade the muscularis propria and extend into the surface of the visceral peritoneum) 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 or less); histological features of aggressiveness, and indeterminate or positive resection margins (NCCN, 2022). Gene expression profiling and circulating tumor DNA (ctDNA) tests are intended to facilitate identifying stage II patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.
 
Of interest, a recent review by Vilar and Gruber has noted that microsatellite instability and mismatch repair (MMR) deficiency in colon cancer may represent confounding factors to be considered in treatment (Vilar, 2010). These factors may identify a minority (15% to 20%) of the population with improved disease-free survival who may derive no benefit or may exhibit deleterious effects from adjuvant fluorouracil/leucovorin-based treatments. Patient microsatellite instability and mismatch repair status may be critically important in how to study, interpret, and use a particular GEP test.
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Multigene expression assay testing and circulating tumor DNA (ctDNA) for predicting recurrent colon cancer is available under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments 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 profile and ctDNA tests for colon cancer currently commercially available include:
 
    • GeneFx Colon (Helomics Therapeutics; also known as ColDx, Almac Diagnostics)
    • Oncotype DX Colon Recurrence Score (Genomic Health)
    • Colvera® ctDNA test (Clinical Genomics)
 
Coding
Effective 3/2015, CPT published a specific CPT code for this service:
 
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

Policy/
Coverage:
Effective August 2020
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Gene expression profiling (OncotypeDX®, ColonPRS®, OncoDefender-CRC, or ColoPrint®) including use for predicting the likelihood of disease recurrence for patients with stage II or III colon cancer following surgery does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, gene expression profiling (OncotypeDX®, ColonPRS®, OncoDefender-CRC, or ColoPrint®), including use for predicting the likelihood of disease recurrence for patients with stage II or III colon cancer following surgery is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
 
Circulating tumor DNA assays including use for predicting the likelihood of disease recurrence (determining the prognosis) for patients with stage II or III colon cancer following surgery does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, circulating tumor DNA assays including use for predicting the likelihood of disease recurrence (determining the prognosis), for patients with stage II or III colon cancer following surgery is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
 
Effective Prior to August 2020
Gene expression profiling (Oncotype DX®, ColonPRS®, OncoDefender-CRC, or ColoPrint®)  including use for predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the 12-gene expression test (Oncotype DX®, ColonPRS®, OncoDefender-CRC, or ColoPrint®), including use for predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery is considered investigational.  Investigational services are exclusions in most member benefit certificates of coverage.
 
Effective prior to May 2012
The 12-gene expression test (Oncotype DX® colon cancer test), including use for predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the 12-gene expression test (Oncotype DX® colon cancer test), including use for predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery is considered investigational.  Investigational services are exclusions in most member benefit certificates of coverage.
 

Rationale:
Validation of genotyping to improve treatment outcomes is a multistep process. In general, important steps in the validation process address the following:
    • Analytic validity: measures technical performance, i.e., whether the test accurately and reproducibly detects the gene markers of interest.
    • Clinical validity: measures the strength of the associations between the selected genetic markers and clinical status.
    • Clinical utility: determines whether the use of genotyping for specific genetic markers to guide treatment decisions improves patient outcomes such as survival or adverse event rate compared to standard treatment without genotyping.
 
Evidence Review
The evidence reviewed for this policy was gathered by searching abstracts from recent meetings held by the American Society of Clinical Oncology (Annual Meeting and Gastrointestinal Cancers Symposium 2009–2010). Abstracts and publications listed on the Genomic Health website were also checked. Authors of relevant abstracts were searched on MEDLINE, but none of the studies presented at meetings have been published in peer-reviewed journals as of the original date of this policy.
 
Development of the 12-gene expression test has been briefly described in abstracts from meetings (Kerr, 2009). A total of 761 candidate genes of possible prognostic value for recurrence or of possible predictive value for treatment were examined by correlating the genes in tumor samples with the clinical outcomes seen in 1,851 patients who had surgery with or without adjuvant 5-FU-based chemotherapy. Gene expression was quantitated from microdissected fixed paraffin-embedded primary colon cancer tissue. Of the 761 candidate genes surveyed, a multivariate analysis including disease severity, stage, and nodal involvement, reduced the genes to a significant seven-gene prognostic signature and a separate six-gene predictive signature. Five reference genes are also included in the assay.
 
The prognostic and predictive signatures were independently evaluated (Kerr, 2009) using tumor samples of a stage II subset of patients from the Quick and Simple and Reliable (QUASAR) study; the subset represented 44% of the entire parent study population and included 711 patients treated with surgery alone and 725 patients treated with adjuvant 5-FU–based chemotherapy following surgery with a mean follow-up of approximately 7 years.
 
The seven-gene prognosis signature, reported as a recurrence score (RS), was a significant and independent predictor of 3-year recurrence risk, which increased continuously with RS. RS scores could separate patients into low-, intermediate-, and high-risk groups. Recurrence risks of disease at 3 years for the low-, intermediate-, and high-risk groups were 12% (9–16%), 18% (13–24%), and 22% (16–29%), respectively. Additional study of the QUASAR data showed that RS and number of lymph nodes examined were independent predictors, with 3-year recurrence risk approximately 5% lower when >12 compared to when <12 nodes were examined (Gray, 2010). Another report compared pathologic markers and gene expression by stage for both stage II and III patients in the four studies conducted to develop the Oncotype DX colon cancer test (O’Connell, 2010). Neither RS nor the majority of genes examined showed significant interaction with stage, indicating a need to examine predictors of recurrence risk in stage III as well as stage II disease.
 
The six-gene predictive signature for 5-FU chemosensitivity did not show significance in the validation study.
 
On January 21, 2010, Genomic Health announced the worldwide commercial availability of its Oncotype DX® colon cancer test. As stated in the press release, “The 12-gene advanced diagnostic test is clinically validated to predict individual recurrence risk in stage II colon cancer patients following surgery.” It is assumed that the test consists of the 7-gene prognostic score plus the 5 reference genes and that the 6-gene predictive signature for chemosensitivity has been removed; however, no details are available on the website.
 
This review of evidence is severely limited by lack of detail because only meeting abstracts and one associated slide presentation were available at the time of writing. None of the studies cited has as yet been published in a peer-reviewed journal. Based on the information available, it seems unlikely that the 12-gene expression test for predicting colon cancer recurrence risk in individual patients could guide clinical decision making because the differences between recurrence risk categories established in the validation study were not sufficiently discriminative and the associated confidence intervals overlapped considerably. For example, a RS of 33 corresponds to a recurrence risk of 16%, which could be low risk, intermediate risk, or high risk when confidence intervals of the category mean estimates are considered. For interpretation, Genomic Health has established RS category ranges for low (<30), intermediate (30-40) and high (>41) risk categories. There is also no information from the validation study on how the test adds to current methods of predicting risk, and how extensively and accurately patients are reclassified by RS after classification by current predictors and compared to their known recurrence outcomes.
 
Summary
 
The only evidence currently available concerning this assay consists of meeting abstracts and one associated slide presentation. The results of one assay validation study (separate from assay development) suggest that the 12-gene expression test recurrence score (RS) increases continuously with increasing risk of colon cancer recurrence, and that RS is independent of other standard clinical and pathological predictors of recurrence risk. However, detailed information regarding the validation study and results is absent due to lack of a fully published, peer-reviewed report. The limited results suggest insufficient discrimination between risk categories to direct post-surgery patient treatment. Additional information available in other meeting presentation abstracts does not address risk category discrimination; nor does it address the extent and accuracy of reclassification by RS after classification by standard predictors. Thus, a complete evaluation awaits full publication of the development and validation studies.
 
The evidence to date is insufficient to permit conclusions concerning the effect of the 12-gene expression test (Oncotype DX® colon cancer test) on health outcomes.
 
2011 Update
A search of the published literature was conducted through March 2011.  There was no new literature identified that would prompt a change in the coverage statement.
 
2012 Update
 
This policy update includes information on the clinical validity and clinical utility of the five currently available assays.
 
Clinical Validity
 
ColonPRS®: Van Laar in 2010 (Van Laar, 2010) reported on a 163-gene expression test using data from 232 colon cancer patients across all stages (I to IV) of disease. Patients were stratified into high risk and low risk, and a second validation performed in 33 stage II and 27 stage III patients. Gene expression classification was reported to show a statistically significant decrease in 5-year disease-free survival in low-risk stage II patients and a trend toward a statistically significant decrease in low-risk stage III patients. This assay ColonPRS® is being marketed as a research use only test and has specific warnings against clinical use. However, the test has recently been acquired by Signal Genetics, L.L.C. It is unclear if the test is or will be marketed commercially for clinical use.
 
Coloprint®: Salazar et al. (Salazar, 2011) in 2010 described the development of an 18-gene expression test (the ColoPrint® test). A total of 188 samples were prospectively collected from patients with colorectal cancers. 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. These were scored for their association with 5-year distant metastasis-free survival. From this pool of genes, an optimal set of 18 nonredundant probes were identified. These were used to construct the classification scores used in the test. Results were dichotomized into a 2-category system identified as high-risk and low-risk scores.
 
In a small independent validation study using a patient cohort of 206 patients, 60% of patients were identified as low risk and 40% as high risk. The population studied, however, had a mixture of patients of different disease stages with only 56% representing stage II tumors. In the evaluation of patients with stage II disease, 63.2% were classified as low risk (with a 5-year recurrence-free survival of 90.9%) and 36.8% were classified as high risk (with 5-year recurrence-free survival of 73.9%). To date, larger validation studies have been published only in abstract form.
 
Colon®: Kennedy et al. in 2011 (Kennedy, 2011) reported on the development of a 634-probe set signature. A training set of 215 patients (143 low risk and 73 high risk) was identified based on disease-free survival at 5 years. The assay was performed using DNA-microarray analysis of formalin-fixed paraffin-embedded 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 and 59 high-risk patients) 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=0.00084) in the high-risk group. The authors noted a further retrospective validation of the test in a large cohort of stage II colon cancer samples collected as part of a clinical trial is planned.
 
OncoDefender®: Lenehan et al. in 2012 (Lenehan, 2012) reported on their development of a 5-gene test, the 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 and 59 with stage II disease; 60 with colon and 14 with rectal cancer). Patients were divided into a training set and a testing 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 receiver operating characteristics curve observed for each gene.
 
External validation was performed on 251 patients with stage I and II colon cancer obtained from an international study set. Patient drop-out from the archived sample banks used was substantial; only 264 (55%) of 484 patients with lymph-node negative colorectal carcinoma (CRC) satisfied the initial clinicopathologic screening. This included a mix of patients with some with both rectal and colon cancer (stage I and Il). The test appeared to distinguish patients at high- versus low-risk of recurrence with a hazard ratio of 1.63, p=0.031. Sensitivity and specificity of the OncoDefender® was compared to National Cancer Consortium Network (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 hazard ratios than observed using the molecular signature. The study alluded to but did not directly address clinical utility.
 
Oncotype DX®: O’Connell et al. (O’Connell, 2010) in 2010 described the development of a 12-gene expression test (the Oncotype DX® colon cancer test). A total of 761 candidate genes of possible prognostic value for recurrence or of possible predictive value for treatment were examined by correlating the genes in tumor samples with the clinical outcomes seen in 1,851 patients who had surgery with or without adjuvant 5-fluorouracil (5-FU)-based chemotherapy. Gene expression was quantitated from microdissected fixed paraffin-embedded primary colon cancer tissue. Of the 761 candidate genes surveyed, a multivariate analysis including disease severity, stage, and nodal involvement, reduced the genes to a 7-gene prognostic signature and a separate 6-gene predictive signature. Five reference genes are also included in the assay.
 
External validation of the algorithm in an independent study, the Quick and Simple and Reliable (QUASAR) study was reported in 2011 (Gray, 2011). The relationship between the 7-gene test’s recurrence score and risk of recurrence was found to be statistically significant with the 3-year risk of recurrence for predefined low-, intermediate-, and high-risk groups to be 12%, 18%, and 22%, respectively. No relationship was identified comparing the 6-gene treatment score results with benefit from chemotherapy.
 
Clinical Utility
No studies of a GEP for determining prognosis of patients with stage II colon cancer have been published demonstrating the effect of testing on overall reclassification of patients when compared to existing methods of risk analysis. There is no published information on the impact from use of GEP results on patient outcomes. In the absence of information showing a direct effect on outcomes or establishing a strong chain of evidence that testing would be expected to have a positive net effect on outcomes, clinical utility of testing remains unclear.
 
Summary
The available evidence indicates that gene expression profile tests for colon cancer can improve risk prediction, particularly regarding the risk of recurrence in patients with stage II colon cancer. However, the evidence to date is insufficient to permit conclusions on how GEP classification compares with other approaches for identifying recurrence risk in stage II patients or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions on how GEP classification compares with other approaches for management of other stages of colon cancer.
 
2013 Update
A literature search conducted using the MEDLINE database through August 2013. There was no new information identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search was conducted using the MEDLINE database through July 2014. There was no new literature identified that would prompt a change in the coverage statement. A summary of the key identified literature is included below.
 
Three studies assessing the use of Oncotype DX® were identified.
 
Venook et al (2013) conducted a validation study using tumor tissue from 690 patients with stage 2 colon cancer who had participated in the Cancer and Leukemia Group B (CALGB) 9581 trial (Venook, 2013).  CALGB 9581 randomized 1713 patients with stage 2 colon cancer to treatment with edrecolomab, an experimental monoclonal antibody, or observation; DFS and overall survival did not differ between treatment groups. Venook et al selected samples stratified by treatment group from those who had tumor tissue available (40% of the original patient sample). The authors used recurrence score cut points of 29 and 39 to determine low-, intermediate-, and high-risk groups; these values differ from the cut points of 30 and 41 validated in the QUASAR study previously described. Estimated 5-year recurrence risk was 12% (95% confidence interval [CI], 10 to 15), 15% (95% CI, 12 to 17), and 18% (95% CI, 14 to 22) in the low-, intermediate-, and high-risk groups, respectively. 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 2 colon cancer who had participated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial (Yothers, 2013).  NSABP C-07 randomized 2409 patients with stage 2 (28%) or stage 3 (72%) colon cancer to adjuvant chemotherapy with 5-FU plus leucovorin (FULV) or oxaliplatin plus FULV (FLOX). Yothers et al randomly selected 50% of patients who had tissue available (total of 892 tissue samples), 264 of whom (30%) had stage 2 cancer. For these patients, estimated 5-year recurrence risks adjusted for treatment (FULV vs FLOX) were 9% (95% CI, 6 to 13) in the Oncotype-defined low-risk group, 13% (95% CI, 8 to 17) in the intermediate-risk group, and 18% (95% CI, 12 to 25) in the high-risk group. Five-year recurrence risk was reduced in high-risk patients who received oxaliplatin compared with those who did not (Kaplan-Meier estimated 5-year recurrence risk, 9% [95% CI, 3 to 25] FLOX vs 23% [95% CI, 12 to 42] FULV), 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 3 patients in any risk class, adjusted 5-year recurrence risk estimates exceeded 15%.
 
No studies of GEP for determining prognosis of patients with stage 2 colon cancer have been published demonstrating the effect of testing on overall reclassification of patients when compared with existing methods of risk analysis. Srivastava et al (2014) published a study showing the effect of Oncotype DX® results on treatment recommendations made according to traditional risk classifiers (Srivastava, 2014). However, this study did not assess survival or recurrence outcomes. Currently, there is no published information on the impact of use of GEP results on patient outcomes. Absent information showing a direct effect on outcomes or establishing a strong chain of evidence that testing has a positive net effect on outcomes, clinical utility of testing remains unclear.
 
Ongoing and Unpublished Clinical Trials
One ongoing trial was identified from online site ClinicalTrials.gov. NCT00903565. The ColoPrint® Assay is being prospectively validated in patients with stage 2 colon cancer in the Prospective Analysis of Risk Stratification by Colo-Print study. Estimations of 3-year relapse rates by ColoPrint, American Society of Clinical Oncology criteria, and independent investigator risk assessment will be compared. The study began in September 2008 with estimated enrollment of 1200 patients. The last verification date for this study was February 2014.
     
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Several validation studies of GEP for colon cancer report that testing provides prognostic information on the risk of recurrence. For patients with a low risk OncotypeDx score, five-year recurrence risk might be as high as 24%. This is likely too high to reasonable withhold adjuvant treatment in patients with stage 2 rectal cancer who would otherwise receive it. Also, the increase in recurrence risk for a high-risk score is modest and it is uncertain whether the degree of increase is sufficient to intensify management. Some studies have reported that GEP testing offers prognostic information in a multivariate analysis. However, no studies have compared GEP testing to other methods of risk stratification for this population. The evidence is insufficient to determine whether GEP testing provides incremental prognostic information over the standard prognostic work-up.
 
Clinical Utility
Brenner and colleagues published a retrospective study of the association between OncotypeDx recurrence score and management decisions (Brenner, 2016). There were 269 patients from one health plan included who had stage II colon cancer, mismatch repair proficient status, and OncotypeDX recurrence scores. The primary outcome measures were changes in management that occurred following OncotypeDx 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 102/269 patients (38%). Of the 102 patients with management changes, there were 76 cases in which the intensity of management was decreased and 26 patients in whom the intensity 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. This type of study does not determine whether patient outcomes are improved as a consequence of the changes in management.
 
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 in not large.
  • Does GEP testing provide incremental prognostic information, compared to the standard clinical workup for prognosis?
Uncertain. There are no well-done studies that compare the prognostic information from GEP testing with 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.
 
Summary: Clinical Utility
Some studies report management changes following GEP testing. However, these studies do not report clinical outcomes and cannot determine whether GEP testing improves health outcomes. An indirect chain of evidence does not demonstrate clinical utility because there are multiple links in the chain which are not intact.
 
The indirect chain of evidence that demonstrates that GEP testing would improve health outcomes is weak. Studies showing management changes as a consequence of testing do not demonstrate whether such changes in management improve outcomes.
 
2017 Update
A literature search conducted through November 2017 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Niedzwiecki and colleagues reported recurrence free interval from 393 patients out of 1738 treated in the Cancer and Leukemia Group B 9581 (CALGB 9581) trial (Niedzwiecki, 2016). 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).
 
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
 
Signatera Assay
Two cohort studies, one that used the Signatera assay, reported an association between positive ctDNA results and risk of recurrence of colon cancer (Reinert, 2019).
 
Reinert et al enrolled 125 patients with Stage I-III colon cancer in a validation study of the Signatera assay (Reinert, 2019). Plasma samples were collected before surgery, at 30 days following surgery, and every 3 months for up to 3 years. The recurrence rate at 3 years was70% in patients with a positive ctDNA test (7 of 10) compared to 11.9% (10 of 84) of those with a negative ctDNA test. In multivariate
analyses, ctDNA status was associated with recurrence after adjusting for clinicopathological risk factors including stage, lymphovascular invasion, and microradical resection status.
 
Wang et al enrolled patients with stage I, II, or II colon cancer and collected samples for ctDNA analyses at 1 month following surgery and then every 3 to 6 months; samples were available for 58 patients (Wang, 2019). The recurrence rate among patients with positive ctDNA levels after surgery was 77% (10 of 13 patients). Of the 45 patients who had negative ctDNA results (16 of whom received adjuvant chemotherapy and 29 who did not), none had a recurrence during a median followup of 49 months (range 11-70 months). Three of 48 patients (6%) who had a positive ctDNA test did not experience recurrence; However, these patients eventually had undetectable ctDNA levels during follow-up.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Oki et al published a prospective observational study in Japan examining the impact of Oncotype Dx Colon Recurrence Score on management decisions for patients with stage II and stage IIIA/IIIB colon cancer (Oki, 2021). The study included 275 patients; 97 patients had stage II colon cancer, and 178 had stage IIIA/IIIB disease. Oncotype Dx Colon Recurrence Score changed treatment decisions in 39.6% of patients. Treatment was decreased in intensity in 32% of study patients (n=88) and increased in intensity for 7.6% of study patients (n=21). Patients with stage IIIA/IIIB cancer had treatment recommendations changed more frequently than patients with stage II cancer (44.9% vs. 29.9%; p=.0148).
 
Three cohort studies have reported an association between positive ctDNA results and risk of recurrence of colon cancer (Young, 2016; Murray, 2018; Symonds, 2020).
 
Young et al enrolled 122 patients with colorectal cancer who had no evidence of residual disease after initial therapy (Young, 2016). In this study, a positive ctDNA test was associated with an increased risk of recurrence. Blood samples were also tested for CEA, and a positive CEA test was also found to be significantly associated with an increased risk of recurrence. Among the 28 patients who had recurrent disease, 9 patients (32%) had a positive CEA test, while 19 (68%) had a positive ctDNA test (p=.002). Among the 94 patients without clinically detectable recurrence, CEA was positive in 6 patients (6%) and ctDNA test was positive in 12 (13%; p=.210). The positive predictive values of ctDNA and CEA were 61.3% and 60%, respectively. The negative predictive values were 90.1% and 82.2%, respectively.
 
Murray et al enrolled 172 patients with invasive colorectal cancer with plasma samples collected within 12 months after surgery (Murray, 2018). In this study, multivariate analysis found that risk of recurrence was increased among patients who had positive ctDNA tests following surgery. Risk of colorectal cancer-related death was also increased among patients who had a positive ctDNA test following surgery, but multivariate analysis could not be performed for this outcome due to the low number of events.
 
Symonds et al examined the association between a positive Colvera test result and recurrence of colorectal cancer in 144 patients who had no evidence of residual disease after surgical resection and/or neoadjuvant chemotherapy (Symonds, 2020). Blood samples were also tested for CEA, and the association between a positive CEA test and recurrent colorectal cancer was assessed. A positive Colvera test was an independent predictor of recurrence, while a positive CEA test was not found to be a significant predictor of recurrence after adjusting for other predictors of recurrence (eg, stage at primary diagnosis). Sensitivity of the Colvera assay for detecting recurrence was significantly greater than the sensitivity of CEA (66% vs. 31.9%, p=.001), but specificity was not significantly different (97.9% vs. 96.4%, p=1.000). The positive predictive value was not significantly different for Colvera and CEA (94.3% vs. 83.3%, p=.262), but the negative predictive value was significantly greater for Colvera (84.4% vs. 71.7%, p<.001).
 
Musher et al conducted an additional prospective cross-sectional observational study in patients undergoing surveillance after definitive therapy for stage II or III colorectal cancer (Musher, 2020). Samples were collected within 6 months of planned radiologic surveillance imaging and tested using the Colvera assay and a CEA assay. A total of 322 patients were included, with 27 experiencing recurrence and 295 not experiencing recurrence. The sensitivities of Colvera and CEA for detecting colorectal cancer recurrence using a single time-point blood test were 63% (17/27) and 48.1% (13/27), respectively (p=.046). The specificities of single time-point Colvera and CEA were 91.5% and 96.3%, respectively (p=.012).
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Tie et al conducted a randomized controlled trial (DYNAMIC) in 455 patients with stage II colon cancer to compare ctDNA-guided treatment and standard clinically guided treatment (Tie, 2022). Chemotherapy was started if ctDNA was positive at 4 or 7 weeks after surgery. For the primary endpoint (recurrence-free survival at 2 years), ctDNA-guided treatment was noninferior to standard treatment (93.5% vs. 92.4%; absolute difference, 1.1%; 95% CI, -4.1 to 6.2). Fewer patients who received ctDNA-guided treatment received adjuvant chemotherapy compared to standard treatment (15% vs. 28%; relative risk, 1.82; 95% CI,1.25 to 2.65).
 
In 2022, the American Society of Clinical Oncology published updated guidance on adjuvant chemotherapy for stage II colon cancer (Baxter, 2022). The guideline stated that there was insufficient evidence on the predictive value of ctDNA to warrant a recommendation, but that a recommendation may be possible in the future if prospective data becomes available.
 
In 2020, an expert panel of the National Cancer Institute (the Colon and Rectal-Anal Task Forces) published a white paper on the use of ctDNA in colorectal cancer (Dasari, 2020). For nonmetastatic colorectal cancer, the paper stated that ctDNA after surgery or completion of adjuvant therapy is highly associated with disease recurrence and can be used as a marker of minimal residual disease.

CPT/HCPCS:
81479Unlisted molecular pathology procedure
81525Oncology (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
81599Unlisted multianalyte assay with algorithmic analysis
84999Unlisted chemistry procedure
88299Unlisted cytogenetic study

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Barrier A, Roser F, Boelle PY et al.(2007) Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling. Oncogene 2007; 26(18):2642-8.

Baxter NN, Kennedy EB, Bergsland E, et al.(2022) Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update. J ClinOncol. Mar 10 2022; 40(8): 892-910. PMID 34936379

Blum C, Graham A, Yousefzadeh M et al.(2008) The expression ratio of Map7/B2M is prognostic for survival in patients with stage II colon cancer. Int J Oncol 2008; 33(3):579-84.

Brenner B, Geva R, Rothney M, et al.(2016) Impact of the 12-gene colon cancer assay on clinical decision making for adjuvant therapy in stage II colon cancer patients. Value Health. Jan 2016;19(1):82-87. PMID 26797240

Dasari A, Morris VK, Allegra CJ, et al.(2020) ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper. Nat Rev Clin Oncol. Dec 2020; 17(12): 757-770. PMID 32632268

Genomic Health Announces Worldwide Availability of the Oncotype DX(R) Colon Cancer Test. Press release. Available at http://investor.genomichealth.com/ReleaseDetail.cfm?ReleaseID=439184

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Kennedy RD, Bylesjo M, Kerr P et al.(2011) Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011; 29(35):4620-6.

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Lenehan PF, Boardman LA, Riegert-Johnson D et al.(2012) Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma. Cancer 2012.

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Musher BL, Melson JE, Amato G, et al.(2020) Evaluation of Circulating Tumor DNA for Methylated BCAT1 and IKZF1 to Detect Recurrence of Stage II/Stage III Colorectal Cancer (CRC). Cancer Epidemiol Biomarkers Prev. Dec 2020; 29(12): 2702-2709. PMID 32958500

Musselwhite LW, May FP, Salem ME, et al.(2021) Colorectal Cancer: In the Pursuit of Health Equity. Am Soc Clin Oncol Educ Book. Mar 2021; 41: 108-117. PMID 34010044

National Cancer Institute (NCI), Surveillance Epidemiology and End Results Program.(2022) Cancer Stat Facts: Colorectal Cancer. n.d.; https://seer.cancer.gov/statfacts/html/colorect.html. Accessed June 22, 2022.

National Comprehensive Cancer Network (NCCN).(2022) Clinical practice guidelines in oncology: colon cancer. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 22, 2022.

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Colon Cancer V.2.2010. Available online at http://www.nccn.org/. Accessed February 2010.

Niedzwiecki D, Frankel WL, Venook AP, et al.(2016) 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

O'Connell MJ, Lavery I, Yothers G et al.(2010) Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010; 28(25):3937-44.

O'Connell MJ, Lavery IC, Gray RG et al.(2010) Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score. American Society of Clinical Oncology Gastrointestinal Cancers Symposium, 2010, Abstract 280.

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Reinert T, Henriksen TV, Christensen E, et al.(2019) Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol. May 09 2019. PMID 31070691

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Srivastava G, Renfro LA, Behrens RJ, et al.(2014) 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

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