Description of Procedure or Service

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. Tumors originate in adenomas or flat dysplasia and evolve into different morphologic patterns with invasion and expansion.

Monoclonal antibodies that bind the epidermal growth factor receptor (EGFR), such as cetuximab, and block its activation have led to significant clinical benefits for metastatic colorectal cancer (mCRC) patients.  Mutations in downstream effectors of the EGFR pathway have been associated with resistance to EGFR antibody chemotherapies.

For guidance on microsatellite instability or tumor mutational burden testing in colorectal cancer, please refer to AHS-M178 Microsatellite Instability and Tumor Mutational Burden Testing.

Related Policies

AHS-M2004 Lynch Syndrome

AHS-M2024 Genetic Testing for Polyposis Syndromes

AHS-M2029 Molecular Testing for Cutaneous Melanoma

AHS-M2178 Microsatellite Instability and Tumor Mutational Burden Testing 

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for testing for colorectal cancer management when it is determined the medical criteria or reimbursement guidelines below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. 

When Testing for Colorectal Cancer Management is covered

1. For all individuals with metastatic colorectal cancer, KRAS, NRAS and BRAF mutation genotyping of the primary or the metastatic tumor is considered medically necessary. 
2. For individuals with metastatic colorectal cancer for whom tumor tissue testing did not identify a mutation in KRAS, NRAS or BRAF, HER2 amplification testing is considered medically necessary. 

When Testing for Colorectal Cancer Management is not covered

For all other situations, not described above, testing for KRAS, NRAS and BRAF mutations is considered investigational.

For all other situations and/or mutations not described above, genotyping of the colorectal cancer tumor is considered investigational.

To determine the prognosis of stage II colon cancer following surgery, gene expression profiling is considered investigational.

Note: For 2 or more gene tests being run on the same platform, please refer to AHS-R2162 Reimbursement Policy.

Policy Guidelines

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 107,320 new cases of colon cancer and 46,950 new cases of rectal cancer for 2025. Overall, there is about a one in twenty-four or twenty-six lifetime risk of developing colorectal cancer based on gender. 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.

Approximately one-quarter of the patients with colon cancer present with stage II disease. 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. 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.

Certain mutations may affect treatment of CRC. For example, the activation of the (EGFR) signaling cascade is associated with colon tumorigenesis; 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. 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. 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.

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.

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. 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.

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. 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.

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.” 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.

Analytical Validity

Cenaj et al. (2019) evaluated the correlation between “ERBB2 amplification by next-generation sequencing (NGS) with HER2 overexpression by immunohistochemistry”. NGS was performed on specimens with 20% or more tumor, and 1300 cases of colorectal cancer were included. ERBB2 amplification was detected in two percent  of cases. HER2 amplification was examined in “15 cases with ERBB2 amplification (six or more copies), 10 with low gain (three to five copies), and 77 copy neutral”. ERBB2 amplification was found to have perfect concordance with HER2 immunochemistry at H-scores of 105 or more. Further, ERBB2 amplification was found to inversely correlate with RAS/RAF mutations. The authors concluded that “NGS-detected ERBB2 amplification highly correlates with HER2 overexpression in CRC”, which may support authors’ original hypothesis that ERBB2 amplification/overexpression may predict response to HER2 inhibitors.

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).” 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.

Pinheiro et al. (2022) studied the analytical validity of using ctDNA as a possible strategy to analyze KRAS and NRAS mutations from patients with metastatic colorectal cancer. The BEAMing Digital PCR (OncoBEAM) and Idylla ctDNA qPCR were compared and the concordance rate was reported. Blood samples from 47 mCRC patients were tested and the overall agreement and concordance rate were noted. "The overall agreement between tumor tissue and ctDNA analyses was 83% and 78.7% using the OncoBEAM and Idylla assays, respectively, with the concordance being 96.2% and 88.5% in naive treatment patients. The overall agreement between OncoBEAM and Idylla ctDNA analyses was 91.7%." The authors conclude that Idylla ctDNA qPCR method is a cheaper alternative with equivalent performance in comparison to the OncoBEAM assay. Analysis of ctDNA can be used to detect “RAS mutations in plasma, either at diagnosis or after progression when considering anti-EGFR treatment rechallenge.”

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.

Douillard et al. (2013) evaluated the effect of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) compared to just FOLFOX4 on patients with varying RAS and BRAF mutations. A total of 639 patients with metastatic CRC without mutations in KRAS exon 2 had at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. A total of 228 patients had neither RAS nor BRAF mutations, and this group was evaluated to have better survival metrics with panitumumab plus FOLFOX4 than the group with just FOLFOX4 (median of 10.8 months progression-free survival and 28.3 months overall survival for panitumumab group vs 9.2 and 20.9 respectively for the group without). However, 296 patients with either a RAS or BRAF mutation were treated with panitumumab plus FOLFOX4, and this group’s survival metrics were lower than the group only treated with FOLFOX4. The RAS/BRAF group treated with panitumumab plus FOLFOX4 had a median of only 7.3 months progression-free survival and 15.3 months overall survival vs 8.0 and 18.0 for the 305 patients treated with only FOLFOX4). The authors concluded that additional RAS mutations predicted a lack of response to panitumumab plus FOLFOX4. 

Therkildsen et al. (2014) performed a meta-analysis of the clinical impact of anti-EGFR treatment on patients with KRAS, NRAS, and BRAF mutations (as well as PIK3CA and PTEN). A total of 22 studies (2395 participants) were evaluated. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival rate (PFS) and overall survival (OS) were calculated. Mutations in KRAS exons 3 and 4 and BRAF predicted poor ORR (0.26 and 0.29 respectively), KRAS, NRAS, and BRAF mutations all led to significantly lower progression-free survival (HR = 2.19, 2.30, and 2.95 respectively) and significantly lower overall survival (HR = 1.78, 1.85, and 2.52 respectively).

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 (OS) 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.

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.”

The prognostic benefit was corroborated by Chang et al. (2021), who found that the BRAF gene mutation was “associated with cancer thrombosis in blood vessels” and was “negatively correlated with the OS [overall survival] rate of CRC patients” in their patient population (n=410) from Central China. Like Fan et al. (2021), KRAS also had the greatest mutation rate at 47.56% in this study, showing more awareness needed for tissue genotyping for mCRC.

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.”

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.

Several studies have evaluated the impact of the gene expression profiling on clinical decision making in certain colon cancer subgroups. Brenner et al. (2016) assessed the clinical impact of the 12-gene Colon Cancer Recurrence Score Assay in treatment of T3 mismatch repair proficient (MMR-P) stage II colon cancer. Out of 269 patients, 102 patients had their treatment changed because of the assay’s results. The authors concluded that testing significantly impacted adjuvant treatment decisions in clinical practice.

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 Srivastava et al. (2014) conducted a prospective study assessing the impact of recurrence score results on physician recommendations regarding adjuvant chemotherapy in T3 MMR-P stage II colon cancer patients. A total of 141 patients were eligible for analysis, and the study concluded that treatment recommendation changes were made for 63 (45%) of patients.

Chang et al. (2020) reviewed the “entire database” of the OncoType Colon Recurrence Score test to identify any age-related differences in Recurrence Score (RS) and single-gene results. A total of 20,478 Stage II and IIIA/B colon cancer patients were included. RS results were categorized into low, medium, and high risk, and single-gene results were organized by median and interquartile ranges. In total 72.5% of all patients and 72.6% of patients under 40 years old were found to have a low-risk RS. However, there were no significant differences in either RS or single-gene results among the four age groups (<40, 40-54, 55-64, >65). Young-onset cancer was also not found to differ by gene expression in individual RS genes. Overall, most patients in stages II or III colon cancer were found to have low-risk disease per the OncoType assay.

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. 52 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.”

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 $3900.00.

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.”

Guidelines and Recommendations

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).”

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).

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.”

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.

National Comprehensive Cancer Network (NCCN)

The guidelines version 1.2025  recommends that “all patients with metastatic colorectal cancer should have tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of a next generation sequencing (NGS) panel (preferred). Patients with any known KRAS mutation (exons 2, 3, and 4) or NRAS mutation (exons 2, 3, 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. Testing can be performed on formalin fixed paraffin embedded tissue (preferred) or blood-based assay.

The NCCN further states that “testing can be performed on the primary CRCs cancers 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. Allele-specific PCR, NGS or immunohistochemistry (IHC) may be used to determine BRAF status.

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 KRAS/NRAS or BRAF mutations.

Routine EGFR testing is not recommended.

Overall, in patients with suspected or proven mCRC, the NCCN recommends molecular testing, including: RAS and BRAF mutations, HER2 amplifications; MMR or MSI status (if not previously done). Testing should be conducted as part of broad molecular profiling, which would identify rare and actionable mutations and fusions such as POLE/POLD1, RET, and NTRK.”

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.”

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 tumor biopsy [I, A] (or through a liquid biopsy in case no tumor 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 tumor or other metastatic sites [III, A]  
• BRAF mutation 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 counseling 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.”

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.”

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

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.” 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.”

Research Committee and the Guidelines Committee of the European Society of Coloproctology (ESCP)

This 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.”

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.

State and Federal Regulations, as applicable

Food and Drug Administration (FDA)

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.

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.

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.

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.”

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 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 formalin-fixed paraffin-embedded (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.”

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.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81210, 81275, 81276, 81311, 81405, 81479, 81525, 81599, 0111U, 0471U, 0498U

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

For Policy Titled: KRAS, NRAS and BRAF Mutation Analysis in Colorectal Cancer

For Policy Re-Titled: Testing for Colorectal Cancer Management

Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers. Jun 2013;5(2):676-713. doi:10.3390/cancers5020676 

Compton C. Pathology and prognostic determinants of colorectal cancer. Updated February 28, 2025. https://www.uptodate.com/contents/pathology-and-prognostic-determinants-of-colorectal-cancer 

De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. The Lancet Oncology. Aug 2010;11(8):753-62. doi:10.1016/s1470-2045(10)70130-3 

Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. Apr 20 2009;27(12):2091-6. doi:10.1200/jco.2009.21.9170 

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. Mar 2017;19(2):187-225. doi:10.1016/j.jmoldx.2016.11.001 

ACS. Key Statistics for Colorectal Cancer. Updated January 16, 2025. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html 

Wang J, Li S, Liu Y, Zhang C, Li H, Lai B. Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population-based analysis. Cancer Med. Jan 2020;9(1):361-373. doi:10.1002/cam4.2673 

El-Deiry WS, Vijayvergia N, Xiu J, et al. Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer biology & therapy. 2015;16(12):1726-37. doi:10.1080/15384047.2015.1113356 

Kopetz S. Adjuvant Chemotherapy for Stage II Colon Cancer. https://pubmed.ncbi.nlm.nih.gov/18494354/ 

NCCN. NCCN Clinical Practice Guidelines in Oncology; Colon Cancer v1.2025. Updated April 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf 

Harris EI, Lewin DN, Wang HL, et al. Lymphovascular invasion in colorectal cancer: an interobserver variability study. The American journal of surgical pathology. Dec 2008;32(12):1816-21. doi:10.1097/PAS.0b013e3181816083 

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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. May 10 2013;31(14):1775-81. doi:10.1200/jco.2012.45.1096 

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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Dec 10 2011;29(35):4611-9. doi:10.1200/jco.2010.32.8732 

Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based a djuvant therapy in colon cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jul 10 2010;28(20):3219-26. doi:10.1200/jco.2009.27.1825 

Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. The New England journal of medicine. Jul 17 2003;349(3):247-57. doi:10.1056/NEJMoa022289 

Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart AK. Revised TN categorization for colon cancer based on national survival outcomes data. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jan 10 2010;28(2):264-71. doi:10.1200/jco.2009.24.0952

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. 23 Jun 2014 2014;doi:10.3109/0284186X.2014.895036 

Clark JW, Sanoff HK. Initial systemic therapy for metastatic colorectal cancer. Updated April 10, 2025. https://www.uptodate.com/contents/initial-systemic-therapy-for-metastatic-colorectal-cancer 

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

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. Aug 10 2017;35(23):2624-2630. doi:10.1200/jco.2016.71.4394 

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. Sep 01 2010;28(25):3937-44. doi:10.1200/jco.2010.28.9538 

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

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

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

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. Dec 10 2011;29(35):4620-6. doi:10.1200/jco.2011.35.4498 

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. Jan 1 2011;29(1):17-24. doi:10.1200/jco.2010.30.1077 

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):127-33. doi:10.1634/theoncologist.2014-0325 

Cenaj O, Ligon AH, Hornick JL, Sholl LM. Detection of ERBB2 Amplification by Next-Generation Sequencing Predicts HER2 Expression in Colorectal Carcinoma. Am J Clin Pathol. Jun 5 2019;152(1):97-108. doi:10.1093/ajcp/aqz031 

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 

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 

Pinheiro M, Peixoto A, Rocha P, et al. KRAS and NRAS mutational analysis in plasma ctDNA from patients with metastatic colorectal cancer by real-time PCR and digital PCR. International Journal of Colorectal Disease. 2022/04/01 2022;37(4):895-905. doi:10.1007/s00384-022-04126-6 

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. Aug 2013;14(8):409-16. doi:10.1111/1751-2980.12063 

Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine. Sep 12 2013;369(11):1023-34. doi:10.1056/NEJMoa1305275 

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. Mar 3 2019;53(1):85-95. doi:10.2478/raon-2019-0013 

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

Chang XN, Shang FM, Jiang HY, et al. Clinicopathological Features and Prognostic Value of KRAS/NRAS/BRAF Mutations in Colorectal Cancer Patients of Central China. Curr Med Sci. Feb 2021;41(1):118-126. doi:10.1007/s11596-021-2326-1 

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 

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. Jun 2022;7(3):100481. doi:10.1016/j.esmoop.2022.100481 

Brenner B, Geva R, Rothney M, et al. Impact of the 12-Gene Colon Cancer Assay on Clinical Decision Making for Adjuvant Therapy in Stage II Colon Cancer Patients. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. Jan 2016;19(1):82-7. doi:10.1016/j.jval.2015.08.013 

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. Feb 2014;30(2):321-8. doi:10.1185/03007995.2013.855183 

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):492-7. doi:10.1634/theoncologist.2013-0401 

Chang GJ, You YNY, Russell CA, et al. Young-Onset Colon Cancer and Recurrence Risk By Gene Expression. J Natl Cancer Inst. Feb 10 2020;doi:10.1093/jnci/djaa019 

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. Feb 12 2022;39(5):59. doi:10.1007/s12032-022-01660-9 

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

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. Jun 2023;7:e2200688. doi:10.1200/po.22.00688 

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. Apr 1 2023;41(10):1943-1948. doi:10.1200/jco.22.02462 

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 

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

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

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

Choosing Wisely Canada. Sixteen Tests and Treatments to Question Updated May 2024. https://choosingwiselycanada.org/recommendation/oncology/ 

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. Apr 2019;21(4):392-416. doi:10.1111/codi.14503 

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

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

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

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 

For Policy Titled: Tumor Tissue Mutation Analysis in Colorectal Cancer

Specialty Matched Consultant Advisory Panel  8/2019

Medical Director review 8/2019

Specialty Matched Consultant Advisory Panel  8/2020

Medical Director review 7/2020

Medical Director review 8/2020

Specialty Matched Consultant Advisory Panel  8/2021

For Policy Re-Titled: KRAS, NRAS and BRAF Mutation Analysis in Colorectal Cancer

Medical Director review 8/2022

For Policy Re-Titled: Testing for Colorectal Cancer Management

Medical Director review 7/2023

Medical Director review 7/2024

Medical Director review 9/2025

Policy Implementation/Update Information

For Policy Titled: KRAS, NRAS, and BRAF Mutation Analysis in Colorectal Cancer 

1/1/2019 New policy developed. BCBSNC will provide coverage for KRAS, NRAS, and BRAF mutation analysis in colorectal cancer when it is determined to be medically necessary and criteria are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)

For Policy Titled: Tumor Tissue Mutation Analysis in Colorectal Cancer

9/10/19 Specialty Matched Consultant Advisory Panel 8/21/19. Reviewed by Avalon 2nd Quarter 2019 CAB. Title changed from KRAS, NRAS, and BRAF Mutation Analysis in Colorectal Cancer to Tumor Tissue Mutation Analysis in Colorectal Cancer. Under “When Covered” section: added “NOTE: For more than 5 gene tests being run on a tumor specimen (i.e. non-liquid biopsy) on the same platform, such as multi-gene panel next generation sequencing, please refer to policy AHS-2109 Molecular Panel Testing of Cancers to Identify Targeted Therapy” for clarity; and removed “E” from BRAF V600E” as other mutations may exist. Added “Related Policies” section. Coding table removed from Billing/Coding section. Medical Director review 8/2019. (lpr)

10/29/19 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Medical Necessity to Reimbursement language, where needed. (hb)

9/8/20 Specialty Matched Consultant Advisory Panel review 8/19/2020. No changes to policy statement. (lpr)

10/1/20 Reviewed by Avalon 2nd Quarter 2020 CAB. Added CPT code 0111U to Billing/Coding section for effective date 10/1/2020. Medical Director review 7/2020. Added related policies. Updated references and policy guidelines. (lpr).

9/7/21 Reviewed by Avalon 2nd Quarter 2021 CAB. Updated Policy Guidelines. References added. Specialty Matched Consultant Advisory panel review 8/18/2021. No change to policy statement. (lpr)

For Policy Re-Titled: KRAS, NRAS and BRAF Mutation Analysis in Colorectal Cancer

9/13/22 Reviewed by Avalon 2nd Quarter 2022 CAB. Medical Director review 8/2022. Removed related policy AHS-M2109 Molecular Panel Testing of Cancers to Identify Targeted Therapy. Updated policy guidelines and references. Under Billing/Coding section: removed CPT 81403 and 88363. Title changed from: Tumor Tissue Mutation Analysis in Colorectal Cancer to: KRAS, NRAS and BRAF Mutation Analysis in Colorectal Cancer. (lpr)

For Policy Re-Titled: Testing for Colorectal Cancer Management

8/15/23 Reviewed by Avalon Q2 2023 CAB. Medical Director review 7/2023. Updated description, policy guidelines and references. Added related policy AHS-M2178. Policy information and criteria from AHS-M2111 Multigene Expression Assay for Predicting Colon Cancer Recurrence was moved into this policy. “When covered and when not covered” sections clarified and edited due to added information from M2111. Added CPT codes 81479, 81525, 81599 to Billing/Coding section. Title changed from: KRAS, NRAS and BRAF Mutation Analysis in Colorectal Cancer to: Testing for Colorectal Cancer Management. (lpr)

9/4/24 Reviewed by Avalon Q2 2024 CAB. Medical Director review 7/2024. Updated related policies, policy guidelines, guidelines and recommendations. Edited “when not covered” section for clarity and edited Note. Added PLA code 0471U. (lpr)

10/1/24 Added PLA code 0498U to Billing/Coding section for 10/1/24 code update. (lpr)

10/15/25 Reviewed by Avalon Q3 2025 CAB. Medical Director review 9/2025. Updated policy guidelines, guidelines and recommendations and references. (lpr)