Description
Colorectal cancer (CRC) involves the accumulation of genetic and epigenetic modifications within pathways that regulate proliferation, apoptosis, and angiogenesis resulting in carcinoma of the colon and rectum.¹ Tumors originate in adenomas or flat dysplasia and evolve into different morphologic patterns with invasion and expansion.²

For guidance on microsatellite instability or tumor mutational burden testing in colorectal cancer, please refer to CAM 342- Microsatellite Instability and Tumor Mutational Burden Testing.

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request. 

1. For all individuals with suspected or proven metastatic colorectal cancer, tissue- or blood-based single gene or multigene panel testing (see Note 1) and HER2 overexpression/amplification testing is considered MEDICALLY NECESSARY.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.

2. For all other situations not described above, genotyping of the colorectal cancer tumor is considered NOT MEDICALLY NECESSARY.
3. To determine the prognosis of stage II colon cancer following surgery, gene expression profiling (e.g., ColDx, Coloprint, Oncotype DX Colon Cancer Assay) is considered NOT MEDICALLY NECESSARY.

NOTES

Note 1: When multigene panel testing is performed in individuals with colon cancer, the panel should at minimum include the following: BRAF, KRAS, NRAS, NTRK1/2/3, POLE/POLD1, and RET. When tissue-based testing is performed, it is recommended that testing should be performed on the metastasis.

Note 2: For two or more gene tests being run on the same platform, please refer to CAM 235-Reimbursement Policy.

Regulatory Status
Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Cetuximab and panitumumab have FDA marketing approval for treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy.

On May 23, 2014, the FDA approved therascreen KRAS RGQ PCR Kit is a real-time qualitative PCR assay used on the Rotor-Gene Q MDx instrument for the detection of seven somatic mutations in the human KRAS oncogene, using DNA extracted from formalin-fixed paraffin-embedded (FFPE), colorectal cancer (CRC) tissue. The therascreen KRAS RGQ PCR Kit is intended to aid in the identification of CRC patients for treatment with Erbitux (cetuximab) and Vectibix (panitumumab) based on a KRAS no mutation detected test result.⁴⁵

On May 7, 2015, the FDA approved cobas KRAS Mutation Test, for use with the cobas® 4800 System. Cobas is a real-time PCR test for the detection of seven somatic mutations in codons 12 and 13 of the KRAS gene in DNA derived from formalin-fixed paraffin-embedded human colorectal cancer (CRC) tumor tissue. The test is intended to be used as an aid in the identification of CRC patients for whom treatment with Erbitux (cetuximab) or with Vectibix (panitumumab) may be indicated based on a no mutation detected result.⁴⁶

On June 29, 2017, the FDA approved PraxisTM Extended RAS Panel as a qualitative in vitro diagnostic test using targeted high throughput parallel sequencing for the detection of 56 specific mutations in RAS genes [KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4)] in DNA extracted from FFPE colorectal cancer (CRC) tissue samples. The Praxis™ Extended RAS Panel is indicated to aid in the identification of patients with colorectal cancer for treatment with Vectibix (panitumumab) based on a no mutation detected test result. The test is intended to be used on the Illumina MiSeqDx instrument.⁴⁷

On November 30, 2017, the FDA approved FoundationOne CDx, which is a next-generation sequencing oncology panel. From the FDA website: “FoundationOne CDx™ (F1CDx) is a next-generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels) and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from FFPE tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies listed Table 1 in accordance with the approved therapeutic product labeling. Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for cancer patients with solid malignant neoplasms. The F1CDx test is a single-site assay performed at Foundation Medicine, Inc.”⁴⁷

In 2021, the ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA) was approved. O/RDx-LCCA is a highly accurate FDA approved IVD assay for the detection of clinically relevant KRAS variants in CRC and EGFR variants in and determination of approved therapy. “The device is a qualitative next generation sequencing based in vitro diagnostic test that uses amplicon-based target enrichment technology for detection of single nucleotide variants (SNVs) and deletions in 2 genes from DNA isolated from FFPE non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) tumor tissue specimens. The test is intended as a companion diagnostic to identify patients with NSCLC or CRC who may benefit from treatment with the targeted therapies.”⁴⁸

Table of Terminology

Rationale 
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States following lung cancer. The American Cancer Society (ACS) estimates 108,860 new cases of colon cancer and 49,990 new cases of rectal cancer for 2026. Overall, there is about a one in twenty-four or twenty-six lifetime risk of developing colorectal cancer based on gender.³ Metastatic colorectal cancer (mCRC), which occurs in 22% of patients with colorectal cancer, has a significantly poorer prognosis than colorectal cancer that has not metastasized. The five-year survival is 14% in patients with distant metastases from CRC, as compared to 71% for all CRC patients.^4,5

Approximately one-quarter of the patients with colon cancer present with stage II disease.⁶ The current National Comprehensive Cancer Network (NCCN) guidelines include adjuvant chemotherapy as a treatment option in this setting, particularly for high-risk stage II patients, as determined by clinical and pathological parameters.⁷ Although some of the routinely used parameters for estimating recurrence risk, such as T-stage and mismatch repair (MMR) status, are well established, they may not be reliable predictors of recurrence risk in this population.^8-13

Certain mutations may affect treatment of CRC. For example, the activation of the EGFR signaling cascade is associated with colon tumorigenesis;¹⁴ therefore, medications such as cetuximab or panitumumab that target the EGFR pathway may be used in treatment of CRC. However, activating mutations in the KRAS oncogene will cause anti-EGFR resistance since these mutations can result in a constitutively active pathway, even with anti-EGFR treatment.¹⁵ Consequently, tumors with mutated KRAS are unresponsive to anti-EGFR therapy. As a result, testing for mutational status as a negative predictive factor for anti-EGFR therapy has become part of routine pathological evaluation for CRC. Other mutations in the RAS oncogene (primarily NRAS) may also lead to the same phenotype.¹⁶ Another gene that may be overexpressed within the EGFR pathway is HER2 (human epidermal growth factor receptor 2). This gene plays a role in activating signal transduction pathways controlling epithelial cell growth. Although HER2 is more traditionally known as a breast cancer-associated gene, up to five percent of colorectal cancer cases are found to overexpress HER2.¹⁵

Another component of the RAS signaling pathway, BRAF, has also been found to affect anti-EGFR treatment. BRAF V600E mutations may also confer a lack of response to anti-EGFR treatment even when paired with a wild-type RAS oncogene. Mutations in this region occur in less than 10% of sporadic CRCs, and the mutation at position 600 is the primary polymorphism found in CRC. Non-V600 BRAF mutations are rarer (composing about 2.2% of patients with metastatic CRC) and confer a generally better prognosis than their V600 mutated counterparts; a study found non-V600 genotypes to lead to better median overall survival and fewer high-grade tumors.¹⁷

Proprietary Testing
Gene expression assays have been commercially produced to predict prognosis of colon cancer. The 12-gene Oncotype DX Colon Cancer Assay (Genomic Health, Inc., Redwood City, CA) is a reverse transcriptase polymerase chain reaction–based assay that provides a Recurrence Score (RS) result.¹⁸ This test assesses the activity level of 12 genes (seven cancer-related genes, five reference genes), and this gene expression is scored from 1-100. This test is intended for resected stage II, MMR-P or stage III A/B colon cancer. Low risk is a score under 30, moderate risk is 31-40, and higher risk is ≥41.^19,20

The ColDx assay (Almac Diagnostics, Craigavon, Northern Ireland) uses microarray technology for assessing the gene expression of 634 genes to stratify patients into low and high recurrence risk groups.²¹ ColDx identified 73 high-risk patients with a hazard ratio of 2.62 during cross validation. In an independent validation, the assay identified high-risk patients with a hazard ratio of 2.53.²²

ColoPrint (Agendia, Amsterdam, The Netherlands) is a gene expression classifier that uses whole-genome expression data of 18 key genes to distinguish patients with low versus high-risk of disease relapse. In a study using 206 fresh frozen tumor tissue samples from 188 patients with stage I through IV CRC, ColoPrint classified “60% of patients as low risk and 40% as high risk,” and was “superior to American Society of Clinical Oncology criteria in assessing the risk of cancer recurrence without prescreening for microsatellite instability.”²³ In a study of 416 stage II colon cancer patients, “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%.” Alternatively, the 2013 NCCN clinical risk factors could not distinguish low and high-risk patients.²⁴

Analytical Validity
Fan, et al. (2021) analyzed the relationship between mismatch repair (MMR) protein, RAS, BRAF, and PIK3CA expression and clinicopathological characteristics in elderly patients with CRC. From 327 patients, the researchers found that “the mutation rates of the KRAS, NRAS, BRAF and PIK3CA genes in elderly CRC patients were 44.95% (147/327), 2.45% (8/327), 3.36% (11/327) and 2.75% (9/327), respectively.” They also identified that “KRAS was closely related to tumor morphology (P = 0.002) but not to other clinicopathological features (P > 0.05), and there were no significant differences between NRAS gene mutation and clinicopathological features (P > 0.05). The BRAF gene mutation showed a significant difference in pathological type, tumor location, differentiation degree and lymph node metastasis (P < 0.05), but was not correlated with sex, tumor size and tumor morphology (P > 0.05).”²⁵ This demonstrates the critical nature of mutation analysis for these specific genes to aid in identifying potential therapies that would better patient prognoses especially in such a vulnerable population like the elderly.

Formica, et al. (2020) examined tumor tissue (T) mutational analysis in terms of discordance with circulating tumor DNA (ctDNA) obtained by liquid biopsy from plasma (PL) and assessed through real-time polymerase chain reaction (PCR). Despite finding concordance for patients with BRAF mutations between the tissue and plasma samples, 20% of patients were RAS discordant. Mutations identified from ctDNA were able to refine the prognosis determined by tissue samples. “RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS [median progression free survival] 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008.” This raises a limitation to using tumor tissue as the mainstay for mutational analysis and considering combining with or replacing tumor tissue genotyping with plasma ctDNA as a measure of prognosis going forward.²⁶

Clinical Utility and Validity
In a meta-analysis by Xu, et al. (2013), a total of 2875 patients were evaluated, with 246 patients having BRAF mutations. The objective response rate (ORR) to EGFR therapy was 18.4% (40/217) in mutant BRAF group and 41.7% (831/1993) in the wild-type BRAF group. The overall risk ratio for the ORR of BRAF mutations compared to wild-type BRAF patients was 0.58. The median progression-free survival (hazard ratio 2.98) and overall survival (hazard ratio: 2.85) were significantly shorter of patients with BRAF mutations compared to patients with wild-type BRAF mutations.²⁷

Rebersek, et al. (2019) investigated the impact of molecular biomarkers on survival and response to first-line therapy in metastatic colorectal cancer patients. The study included 154 patients with 42% harboring KRAS mutations and 3% harboring BRAF mutations. Median overall survival was found to be 56.5 months for wild-type KRAS patients and 58 months for mutated KRAS patients. Median OS for mutated exon 12 patients was 57 months compared to 44 months for mutated exon 13 patients. Wild-type KRAS was found to affect the response to first-line systemic therapy, whereas no other parameters were found to affect response.²⁸

Sartore-Bianchi, et al. (2019) investigated the effect of HER2 positivity on anti-EGFR treatment. A total of 100 patients HER2-positive (of 1485 wild-type KRAS exon 2 patients) with metastatic colorectal cancer were included. The authors found that HER2-positive patients had more frequent lung metastases (odds ratio [OR] = 2.04) and higher tumor burden (OR = 1.48). The 79 HER2-positive patients given anti-EGFR treatment were also found to have poorer clinical outcomes, with lower objective response rate (31.2% compared to 46.9% for all others) and lower progression-free survival (5.7 months vs seven months). The authors concluded that HER2 testing should be offered because “occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features.”²⁹

Loree, et al. (2021) characterized the clinical prevalence of atypical KRAS/NRAS mutations in metastatic colorectal cancer. The authors evaluated tissue and DNA samples from 9,485 patients to characterize atypical RAS variants using an in vitro cell-based assay, studying the signaling changes across mutations. According to the results, "KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC.” Of the 57 atypical RAS variants, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. The authors concluded that "KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant.”³⁰

Benavides, et al. (2022) studied how effective liquid biopsy-tailored assays were in identifying guideline-recommended biomarkers, including RAS and BRAF, in comparison to standard of care tissue genotyping for patients newly diagnosed with mCRC. To quantify the effectivity of liquid biopsy assays for biomarkers, the researchers utilized the Guardant360 for comprehensive ctDNA analysis, and OncoBEAM for targeted RAS and BRAF analysis. Among the 155 patients included in this prospective study, physician discretion standard of care tissue genotyping identified guideline-recommended biomarkers in 52.9% of patients, in comparison to the 56.8% from the comprehensive Guardant360 ctDNA analysis and 44.5% from targeted ctDNA analysis by OncoBEAM. An additional 19.5% more samples were included in the ctDNA assays “by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives.” The complete processing of ctDNA assays was faster (10 days versus 27 days on median) and maintained accuracy even 10 days after sample collection (52.0% vs 10.2%). This could allow inclusion of ctDNA genotyping in the care of patients with mCRC and could enable accelerated personalized treatment regimens for patients with the quick turnaround and comparable results to current practices.³¹

Cartwright, et al. (2014) performed a web-based survey evaluating the impact of the 12-gene Colon Cancer Recurrence Score Assay in stage II colon cancer patients. The authors surveyed 346 oncologists about their use of the Oncotype DX assay; the survey included questions about courses of treatment before and after using the assay and the stage of cancer their patient had. The authors found that 29% of treatment recommendations were changed for patients receiving Recurrence Score testing.³²

Allar, et al. (2022) evaluated how the OncoType Colon Recurrence Score influences clinical practice. The study included 105 patients with stage IIa colon cancer and investigated the association between the RS and the decision to offer adjuvant chemotherapy after resection. Fifty-two patients underwent RS testing, seven (13%) of whom received adjuvant chemotherapy. The authors found no significant effect or clear association of RS on the odds of undergoing chemotherapy. The authors conclude that “RS was not associated with the decision to start adjuvant chemotherapy” and suggest that “the RS should not be obtained in patients with stage IIa colon cancer.”³³

Chaudhari and Issa (2022) conducted a study to compare the cost-effectiveness of various genomic tests used to prognosticate stage II colorectal cancer patients. The researchers compared a 12-gene assay, 18-gene expression assay, 482-gene signature assay, and Immunoscore assay in a hypothetical cohort to investigate recurrence risk and death. Using a Markov model, the authors found that “the cost of the Immunoscore assay strategy in stage II colorectal cancer patients was estimated to be US $23,564 with a gain of 3.903 quality-adjusted life years (QALYs) as compared with the 12-gene assay strategy at US $24,545 and 3.903 QALYs; the 18-gene assay strategy at US $28,374 and 3.623 QALYs; and the 482-gene signature treatment strategy at US $33,315 with 3.704 QALYs.” This, along with further analysis, led to the conclusion that the Immunoscore assay may be the “dominant strategy,” in that it may reduce costs associated with treatment in long-term, but for the gene expression signature assays alone, the 12-gene assay may generate more cost savings than the 18-gene expression assay, equivalent to $3900.³⁴

Aoki, et al. (2023) studied the validity of NGS-based ctDNA genotyping for RAS and BRAF V600E mutation assessment to guide therapy for metastatic colorectal cancer. The study included 212 mCRC patients. The authors compared NGS-cased ctDNA genotyping results with the results of validated PCR-based tissue testing, specifically looking at the concordance rate, sensitivity, and specificity. For RAS, the concordance rate was 92.5%, the sensitivity was 88.7%, and the specificity was 97.2%. For BRAF V600E, the concordance rate was 96.2%, the sensitivity was 88.0%, and the specificity was 97.3%. The authors then investigated efficacy of anti-EGFR and BRAF-targeted therapies based on ctDNA results. The progression-free survival pf anti-EGFT therapy was 12.9 months, and the progression-free survival of BRAF-targeted treatment was 3.7 months. The authors concluded that “ctDNA genotyping effectively detected RAS/BRAF mutations” and “clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC.”³⁵

American Society of Clinical Oncology (ASCO)
The ASCO published an endorsement of the College of American Pathologist Guidelines, recommending:

• “For patients with CRC, being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-immunohistochemistry (IHC) and/or microsatellite instability (MSI) by polymerase chain reaction (PCR) for the detection of DNA MMR defects. Although MMR-IHC or MSI by PCR is preferred, pathologists may use a validated MSI by next-generation sequencing (NGS) assay for the detection of DNA MMR defects. Note: MSI by NGS assay must be validated against MMR-IHC or MSI by PCR and must show equivalency. (Strong recommendation).”
• “For all cancer patients being considered for immune checkpoint inhibitor therapy based on defective MMR, pathologists should not use tumor mutation burden (TMB) as a surrogate for the detection of DNA MMR defects. If a tumor is identified as TMB-high, pathologists may perform IHC and/or MSI by PCR to determine if high TMB is secondary to MMR deficiency. (Strong recommendation).”
• “For cancer patients being considered for immune checkpoint inhibitor therapy, if a MMR deficiency consistent with Lynch syndrome is identified in the tumor, pathologists should communicate this finding to the treating physician. (Strong recommendation).”³⁶

Similar to the guideline above, in 2024 ASCO released management of locally advanced rectal cancer guidelines and included the following recommendation:

• “Patients with locally advanced rectal cancer should be assessed for MSI or MMR status prior to commencement of treatment (good practice statement).”³⁷

American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology
These joint guidelines focus on “Molecular Biomarkers for the Evaluation of Colorectal Cancer.” They list the following recommendations for KRAS, NRAS, and BRAF for CRC:

• “Patients with CRC considered for anti-EGFR therapy must receive RAS mutational testing. Mutational analysis should include KRAS and NRAS codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and 146 of exon 4 (expanded or extended RAS).”
• “BRAF p.V600 (BRAF c. 1799 [p.V600]) mutational analysis should be performed in CRC tissue in patients with CRC for prognostic stratification.”
• “There is insufficient evidence to recommend BRAF c.1799 p.V600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors.”³⁸

The joint guidelines state that further research is required to study the clinical validity and utility of gene expression profiling assays in colon cancer patients.³⁸

National Comprehensive Cancer Network (NCCN)
The guidelines version 1.2026 recommends that “all patients with metastatic CRC should have tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of MGPT [multigene panel testing] at initial diagnosis of metastatic disease. Patients with any known KRAS mutation (exons 2, 3, and 4) or NRAS mutation (exons 2, 3, and 4) should not be treated with either cetuximab or panitumumab, unless given as part of a regimen targeting a KRAS G12C mutation. BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor.”

The NCCN guidelines state that testing for KRAS, NRAS and BRAF mutations should be performed only in laboratories that are CLIA-1988 certified as qualified to perform “high-complexity clinical laboratory (molecular pathology) testing.” “No specific methodology is recommended.” 

The NCCN further states that “testing can be performed on the primary CRCs and/or the metastasis, as literature has shown that the KRAS, NRAS, and BRAF mutations are similar in both specimen types.”

The BRAF genotyping of tumor tissue is recommended at stage IV disease.

The NCCN notes that “HER2 is rarely amplified/overexpressed in CRC (approximately 3% overall), but the prevalence is higher in RAS/BRAF–wild-type tumors (reported at 5%–14%).” “HER2-targeted therapies are now recommended in patients with tumors that are RAS/BRAF wild-type and with HER2 overexpression.” Therefore, the NCCN now recommends testing for HER2 amplifications in patients with metastatic CRC. However, HER2 testing is not indicated in patients with known RAS or BRAF mutations.⁷

Routine EGFR testing is not recommended.⁷

Overall, in patients with suspected or proven mCRC, the NCCN recommends "Biomarker testing ordered as rapidly as possible following diagnosis, including: KRAS, NRAS, and BRAF V600E mutations; HER2 (ERBB2) overexpression/amplification; MMR or MSI status (if not previously done). Testing should be conducted as part of multigene panel testing (MGPT), which would identify rare and actionable mutations and gene fusions such as POLE/POLD1, RET, and NTRK 1/2/3.”⁷

Regarding the OncoType DX colon cancer assay, the NCCN remarks that clinical validation in patients with stages II or III cancer from the QUASAR and NSABP clinical trials shows that “recurrence scores are prognostic for recurrence, DFS [disease free survival], and OS [overall survival] in stage II and stage III colon cancer but are not predictive of benefit to adjuvant therapy.” ColoPrint, an 18-gene classifier for recurrence risk, was also found to independently predict recurrence risk and is currently being validated to predict 3-year relapse rates in patients with stage II colon cancer in a prospective trial. Similarly, ColDx, a microarray based multigene assay, was found to independently predict recurrence risk. However, despite these tests’ ability to further inform risk of recurrence, the panel questions the value added. The panel also noted that “evidence of predictive value in terms of the potential benefit of chemotherapy is lacking” and that “there are insufficient data to recommend the use of multigene assays, Immunoscore, or post-surgical ctDNA to estimate risk of recurrence or determine adjuvant therapy.”⁷

European Society for Medical Oncology (ESMO)
In its 2023 guidelines with some September 2024 updates, ESMO recommends the following for mCRC genetic testing:

• “Determining the RAS mutational testing on a tumour biopsy [I, A] (or through a liquid biopsy in case no tumour sample is available [II, B]) is mandatory to guide the best treatment decision.
• Testing for mismatch repair (MMR) status and KRAS, NRAS exon 2, 3, and 4 as well as BRAF mutations is recommended in all patients at the time of mCRC diagnosis [I, A]
• RAS testing is mandatory before treatment with anti-EGFR mAbs and can be carried out on either the primary tumour or other metastatic sites [III, A]
• BRAF V600E mutations [ESCAT: I-A] status should be assessed simultaneously with the evaluation of RAS, for prognostic assessment [I, B] and for the option of treatment with targeted therapy.
• DMMR/MSI-H [ESCAT: I-A, if detection by NGS] testing in metastatic colorectal cancer can assist in genetic counselling for Lynch syndrome [II, B]

, and is recommended as the initial molecular work-up in metastatic disease for its predictive value for the use of immune checkpoint inhibitors [I, A].

• Identification of HER2 overexpression (by IHC) and/or HER2 amplification [ESCAT: II-B] is recommended in RAS-wt patients to detect those who may benefit from targeted therapy.”^39,40

In 2025, EMSO updated the metastatic colorectal cancer living guideline. The guidelines recommend:

• “Testing for MMR status [if detection by NGS] and KRAS, NRAS exon 2, 3 and 4 and BRAF mutation is recommended in all patients at the time of metastatic colorectal cancer diagnosis.”
• “RAS testing is mandatory before treatment with anti-EGFR monoclonal antibodies and can be carried out on either the primary tumour or other metastatic sites.”
• “BRAF V600E mutations status should be assessed simultaneously with the evaluation of RAS, for prognostic assessment and for the option of treatment with targeted therapy.”
• “DMMR/MSI-H [ if detection by NGS] testing in metastatic colorectal cancer can assist in genetic counselling for Lynch syndrome, and is recommended as the initial molecular work-up in metastatic disease for its predictive value for the use of immune checkpoint inhibitors.”
• “Identification of HER2 overexpression (by IHC) and/or HER2 amplification is recommended in RAS-wt patients to detect those who may benefit from targeted therapy.”
• “When multigene tumour NGS is available and applicable, testing for KRAS G12C, and POLE mutations as well as for genomic aberrations for which targeted therapeutics are approved in tumour-agnostic indications [NTRK fusions, RET fusions, TMB-H] is advised.”
• “Testing of other biomarkers including ALK and ROS1 gene fusions [ESCAT: III-A], mutations of PIK3CA and HER2 activating mutations is not recommended outside clinical trials.”
• “Testing for dihydropyrimidine dehydrogenase deficiency must be conducted before initiating 5-FU-based chemotherapy.”⁴¹

With regards to localized colon cancer, ESMO states that “besides MSI status, other genetic markers, e.g. RAS and BRAF mutations are not recommended for the routine assessment of risk of recurrence in non-metastatic patients, based on their lack of utility in the adjuvant decision-making process.”⁴²

In 2023 guidelines, ESMO does not provide recommendations for using gene expression profiling assays for prognosticating patients with stage II colon cancer.³⁹

Choosing Wisely Canada
Choosing Wisely Canada lists “sixteen tests and treatments to question” in their oncology recommendations. In this list, they recommend: “Don’t perform routine colonoscopic surveillance every year in patients following their colon cancer surgery; instead, frequency should be based on the findings of the prior colonoscopy and corresponding guidelines.”⁴³ The guideline goes on to add that “typical colonoscopic surveillance following colon cancer surgery consists of a colonoscopy at one year; thereafter it should not typically exceed every 3 years following detection of an advanced polyp, or every 5 years following a normal exam or one showing small polyps.”⁴³

Research Committee and the Guidelines Committee of the European Society of Coloproctology (ESCP)
IThis systematic review was performed by the committee to assess the consensus levels “in guidelines from member countries of the European Society of Coloproctology, with supporting evidence.” This review focuses on follow-up strategies for patients “after treatment with curative intent of nonmetastatic colorectal cancer.”⁴⁴

In this review, the committee concluded that “laboratory tests other than CEA [carcinoembryonic antigen] should not be part of follow-up,” although it noted that only eight of 21 guidelines reviewed addressed this topic.⁴⁴

References

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14.  Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. review-article. 2014;doi:10.3109/0284186X.2014.895036

15.  Clark JW, Sanoff HK. Initial systemic therapy for metastatic colorectal cancer. Updated March 17, 2026. https://www.uptodate.com/contents/initial-systemic-therapy-for-metastatic-colorectal-cancer

16.  Frucht H, Lucas AL. Molecular genetics of colorectal cancer. Updated November 20, 2024. https://www.uptodate.com/contents/molecular-genetics-of-colorectal-cancer

17.  Jones JC, Renfro LA, Al-Shamsi HO, et al. (Non-V600) BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(23):2624-2630. doi:10.1200/jco.2016.71.4394

18.  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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(25):3937-44. doi:10.1200/jco.2010.28.9538

19.  Oncotype. Oncotype DX Colon Recurrence Score® test. https://www.oncotypeiq.com/en-US/colon-cancer/healthcare-professionals/oncotype-dx-colon-recurrence-score/about-the-test

20.  Oncotype. Explore the Results. https://www.oncotypeiq.com/en-US/colon-cancer/healthcare-professionals/oncotype-dx-colon-recurrence-score/interpreting-the-results

21.  Almac Group. ColDx. https://www.almacgroup.com/diagnostics/portfolio-overview/coldx/

22.  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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(35):4620-6. doi:10.1200/jco.2011.35.4498

23.  Salazar R, Roepman P, Capella G, et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(1):17-24. doi:10.1200/jco.2010.30.1077

24.  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. 2015;20(2):127-33. doi:10.1634/theoncologist.2014-0325

25.  Fan J-Z, Wang G-F, Cheng X-B, et al. Relationship between mismatch repair protein, RAS, BRAF, PIK3CA gene expression and clinicopathological characteristics in elderly colorectal cancer patients. World J Clin Cases. 2021;9(11):2458-2468. doi:10.12998/wjcc.v9.i11.2458

26.  Formica V, Lucchetti J, Doldo E, et al. Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients-The Importance of Tissue/Plasma Discordant Cases. J Clin Med. 2020;10(1):87. doi:10.3390/jcm10010087

27.  Xu Q, Xu AT, Zhu MM, Tong JL, Xu XT, Ran ZH. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a meta-analysis. Journal of digestive diseases. 2013;14(8):409-16. doi:10.1111/1751-2980.12063

28.  Rebersek M, Mesti T, Boc M, Ocvirk J. Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients. Radiol Oncol. 2019;53(1):85-95. doi:10.2478/raon-2019-0013

29.  Sartore-Bianchi A, Amatu A, Porcu L, et al. HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer. Oncologist. 2019;24(10):1395-1402. doi:10.1634/theoncologist.2018-0785

30.  Loree JM, Wang Y, Syed MA, et al. Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer. Clinical Cancer Research. 2021;27(16):4587-4598. doi:10.1158/1078-0432.Ccr-21-0180

31.  Benavides M, Alcaide-Garcia J, Torres E, et al. Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer. ESMO Open. 2022;7(3):100481. doi:10.1016/j.esmoop.2022.100481

32.  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. Current medical research and opinion. 2014;30(2):321-8. doi:10.1185/03007995.2013.855183

33.  Allar BG, Messaris E, Poylin VY, Schlechter BL, Cataldo TE. Oncotype DX testing does not affect clinical practice in stage IIa colon cancer. Med Oncol. 2022;39(5):59. doi:10.1007/s12032-022-01660-9

34.  Chaudhari VS, Issa AM. Cost-effectiveness of precision molecular diagnostic tests for stage II colorectal cancer. Ann Transl Med. 2022;10(23):1260. doi:10.21037/atm-2022-77

35.  Aoki Y, Nakamura Y, Denda T, et al. Clinical Validation of Plasma-Based Genotyping for RAS and BRAF V600E Mutation in Metastatic Colorectal Cancer: SCRUM-Japan GOZILA Substudy. JCO Precis Oncol. 2023;7:e2200688. doi:10.1200/po.22.00688

36.  Vikas P, Messersmith H, Compton C, et al. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of College of American Pathologists Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;41(10):1943-1948. doi:10.1200/jco.22.02462

37.  Scott AJ, Kennedy EB, Berlin J, et al. Management of Locally Advanced Rectal Cancer: ASCO Guideline. Journal of Clinical Oncology. 2024;42(28):3355-3375. doi:10.1200/jco.24.01160

38.  Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. The Journal of molecular diagnostics : JMD. 2017;19(2):187-225. doi:10.1016/j.jmoldx.2016.11.001

39.  Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32. doi:10.1016/j.annonc.2022.10.003

40.  ESMO. ESMO Metastatic Colorectal Cancer Living Guideline. https://www.esmo.org/living-guidelines/esmo-metastatic-colorectal-cancer-living-guideline

41.  EMSO. Diagnosis, Pathology and Molecular Biology. https://www.esmo.org/guidelines/living-guidelines/esmo-metastatic-colorectal-cancer-living-guideline/diagnosis

42.  Argilés G, Tabernero J, Labianca R, et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(10):1291-1305. doi:10.1016/j.annonc.2020.06.022

43.  Choosing Wisely Canada. Sixteen Tests and Treatments to Question https://choosingwiselycanada.org/recommendation/oncology/

44.  Bastiaenen VP, Hovdenak Jakobsen I, Labianca R, et al. Consensus and controversies regarding follow-up after treatment with curative intent of nonmetastatic colorectal cancer: a synopsis of guidelines used in countries represented in the European Society of Coloproctology. Colorectal Dis. 2019;21(4):392-416. doi:10.1111/codi.14503

45.  FDA. Summary of Safety and Effectiveness Data (SSED). https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110027B.pdf

46.  FDA. Summary of Safety and Effectiveness Data (SSED). https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140023B.pdf

47.  FDA. Summary of Safety and Effectiveness Data (SSED). https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160038B.pdf

48.  FDA. ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA). https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pma&id=454588

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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