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 (Bardhan & Liu, 2013). Tumors originate in adenomas or flat dysplasia and evolve into different morphologic patterns with invasion and expansion (Compton, 2023).

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 (De Roock et al., 2010). Mutations in downstream effectors of the EGFR pathway have been associated with resistance to EGFR antibody chemotherapies (Allegra et al., 2009; Compton, 2022; Sepulveda et al., 2017). 

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

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.

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.

3. For all other situations not described above, testing for KRAS, NRAS, and BRAF mutations is considered NOT MEDICALLY NECESSARY.
4. To determine the prognosis of stage II colon cancer following surgery, gene expression profiling is considered NOT MEDICALLY NECESSARY.

NOTES:

Note: For 5 or more gene tests being run on the same platform, please refer to CAM 235 Reimbursement Policy.

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 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer for 2022. Overall, there is a ~4% lifetime risk of developing colorectal cancer (ACS, 2023). Metastatic colorectal cancer (mCRC), which occurs in 22% of patients with colorectal cancer, has a significantly poorer prognosis than colorectal cancer that hasn’t metastasized. The five-year survival is 14% in patients with distant metastases from CRC, as compared to 71% for all CRC patients (El-Deiry et al., 2015; Wang et al., 2020).

Approximately one-quarter of the patients with colon cancer present with stage II disease (Kopetz, 2008). 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 (NCCN, 2023b). 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 (Gray et al., 2011; Gunderson et al., 2010; Harris et al., 2008; Ribic et al., 2003; Sargent et al., 2010; Venook et al., 2013). 

Certain mutations may affect treatment of CRC. For example, the activation of the epidermal growth factor receptor (EGFR) signaling cascade is associated with colon tumorigenesis (Therkildsen et al., 2014); 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 (Clark & Sanoff, 2023). 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 (Frucht & Lucas, 2022). 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 (Clark & Sanoff, 2023). 

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 (Jones et al., 2017).

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 (O'Connell et al., 2010). This test assesses the activity level of 12 genes (7 cancer-related genes, 5 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 (Oncotype, 2020a, 2020b). 

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 (Kennedy et al., 2011).

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” (Salazar et al., 2011). 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 (Kopetz et al., 2015). 

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 2% 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 (Cenaj et al., 2019).

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)” (Fan et al., 2021). 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 (Formica et al., 2020). 

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%" (Pinheiro et al., 2022). 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” (Pinheiro et al., 2022). 

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 (Xu et al., 2013).

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. 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. 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 (Douillard et al., 2013).

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) (Therkildsen et al., 2014).

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 (Rebersek et al., 2019).

Sartore-Bianchi et al. (2019) investigated the effect of HER2 positivity on anti-EGFR treatment. 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 7 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” (Sartore-Bianchi et al., 2019).

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 (Chang et al., 2021).

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” (Loree et al., 2021).

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 (Brenner et al., 2016). 

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 (Cartwright et al., 2014). 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 (Srivastava et al., 2014). 

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. 20478 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. 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 (Chang et al., 2020).

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” (Allar et al., 2022).

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 (Chaudhari & Issa, 2022).

American Society of Clinical Oncology (ASCO) 
ASCO published a Provisional Clinical Opinion (PCO) that states “RAS mutational testing of colorectal carcinoma tissue should be performed in a Clinical Laboratory Improvement Amendments-certified laboratory for all patients who are being considered for anti-EGFR MoAb therapy.” ASCO recommends that “mutational analysis should include KRAS and NRAS codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and 146 of exon 4. The weight of current evidence indicates that anti-EGFR MoAb therapy (currently cetuximab and panitumumab) should only be considered for treatment of patients with mCRC who are identified as having tumors with no mutations detected after such extended RAS mutation analysis” (Allegra et al., 2016).

This guideline was archived and replaced by Sepulveda et al. (2017) (ASCO).

In 2020, ASCO published a guideline titled “Treatment of Patients With Late-Stage Colorectal Cancer”. ASCO recommends that all patients with mCRC should be tested for key molecular markers (when possible) if targeted treatments are available. RAS and BRAF are mentioned as examples of molecular markers (Chiorean et al., 2020).

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

• “Colorectal carcinoma patients being 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 colorectal cancer tissue in patients with colorectal carcinoma 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” (Sepulveda et al., 2017).

National Comprehensive Cancer Network (NCCN)
The guidelines version 1.2023 recommend that “all patients with metastatic colorectal cancer should have tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of an NGS panel. Patients with any known KRAS mutation (exon 2, 3, and 4) or NRAS mutation (exon 2, 3, and 4) should not be treated with either cetuximab or panitumumab. 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 colorectal cancers and/or the metastasis, as literature has shown that the KRAS, NRAS, and BRAF mutations are similar in both specimen types.”

BRAF genotyping of tumor tissue is recommended at stage IV disease. Allele-specific polymerase-chain reaction (PCR), NGS, or immunohistochemistry (IHC) may be used to determine BRAF status. 

The NCCN notes that HER2 may be overexpressed in RAS/BRAF wild-type tumors despite being rarely amplified/overexpressed in CRC (~3% overall). 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 (NCCN, 2023a).

Routine EGFR testing is not recommended (NCCN, 2023a). 
Overall, in patients with mCRC, the NCCN recommends “determination of tumor gene status for RAS and BRAF mutations and HER2 amplifications (individually or as part of tissue- or blood-based NGS panel” and “determination of tumor [mismatch repair] or [microsatellite instability] status (if not previously done)” (NCCN, 2023a).

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 multi-gene assays, Immunoscore, or post-surgical ctDNA to estimate risk of recurrence or determine adjuvant therapy” (NCCN, 2023b).

European Society for Medical Oncology (ESMO)
In its 2023 guidelines, 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].
• Identification of human epidermal growth factor receptor (HER2) amplification by immunohistochemistry (IHC) or FISH [fluorescence in-situ hybridization] is recommended in RAS wild-type (wt) patients to detect those who may benefit from HER2 blockade [III, B].
• 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 mutation status should be assessed simultaneously with the evaluation of RAS, for prognostic assessment [I, B] and for the option of treatment with cetuximab-encorafenib [I, A]. 
• dMMR [deficient mismatch repair]/MSI testing in mCRC can assist in genetic counselling for Lynch syndrome [II, B].
• dMMR/MSI status is also recommended as the initial molecular work-up in metastatic disease for its predictive value for the use of ICIs [immune checkpoint inhibition] [I, A]” (Cervantes et al., 2023).

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” (Argilés et al., 2020).

In their newly released guidelines, ESMO does not provide recommendations for using gene expression profiling assays for prognosticating patients with stage II colon cancer (Cervantes et al., 2023).

American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology Joint Guidelines
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 (Sepulveda et al., 2017).

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” (Bastiaenen et al., 2019).

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 8 of 21 guidelines reviewed addressed this topic (Bastiaenen et al., 2019).

Table of Terminology

References: 

1. ACS. (2023, January 13). Key Statistics for Colorectal Cancer. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html
2. Allar, B. G., Messaris, E., Poylin, V. Y., Schlechter, B. L., & Cataldo, T. E. (2022). Oncotype DX testing does not affect clinical practice in stage IIa colon cancer. Med Oncol, 39(5), 59. https://doi.org/10.1007/s12032-022-01660-9 
3. Allegra, C. J., Jessup, J. M., Somerfield, M. R., Hamilton, S. R., Hammond, E. H., Hayes, D. F., McAllister, P. K., Morton, R. F., & Schilsky, R. L. (2009). 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. J Clin Oncol, 27(12), 2091-2096. https://doi.org/10.1200/jco.2009.21.9170 
4. Allegra, C. J., Rumble, R. B., Hamilton, S. R., Mangu, P. B., Roach, N., Hantel, A., & Schilsky, R. L. (2016). Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol, 34(2), 179-185. https://doi.org/10.1200/jco.2015.63.9674 
5. Argilés, G., Tabernero, J., Labianca, R., Hochhauser, D., Salazar, R., Iveson, T., Laurent-Puig, P., Quirke, P., Yoshino, T., Taieb, J., Martinelli, E., & Arnold, D. (2020). Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 31(10), 1291-1305. https://doi.org/10.1016/j.annonc.2020.06.022 
6. ASCO. https://www.asco.org/research-guidelines/quality-guidelines/guidelines/gastrointestinal-cancer#/9766 
7. Bardhan, K., & Liu, K. (2013). Epigenetics and colorectal cancer pathogenesis. Cancers (Basel), 5(2), 676-713. https://doi.org/10.3390/cancers5020676 
8. Bastiaenen, V. P., Hovdenak Jakobsen, I., Labianca, R., Martling, A., Morton, D. G., Primrose, J. N., Tanis, P. J., & Laurberg, S. (2019). 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, 21(4), 392-416. https://doi.org/10.1111/codi.14503 
9. Benavides, M., Alcaide-Garcia, J., Torres, E., Gil-Calle, S., Sevilla, I., Wolman, R., Durán, G., Álvarez, M., Reyna-Fortes, C., Ales, I., Pereda, T., Robles, M., Kushnir, M., Odegaard, J., Faull, I., & Alba, E. (2022). 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, 7(3), 100481. https://doi.org/10.1016/j.esmoop.2022.100481 
10. Brenner, B., Geva, R., Rothney, M., Beny, A., Dror, Y., Steiner, M., Hubert, A., Idelevich, E., Gluzman, A., Purim, O., Shacham-Shmueli, E., Shulman, K., Mishaeli, M., Man, S., Soussan-Gutman, L., Tezcan, H., Chao, C., Shani, A., & Liebermann, N. (2016). Impact of the 12-Gene Colon Cancer Assay on Clinical Decision Making for Adjuvant Therapy in Stage II Colon Cancer Patients. Value Health, 19(1), 82-87. https://doi.org/10.1016/j.jval.2015.08.013 
11. Cartwright, T., Chao, C., Lee, M., Lopatin, M., Bentley, T., Broder, M., & Chang, E. (2014). Effect of the 12-gene colon cancer assay results on adjuvant treatment recommendations in patients with stage II colon cancer. Curr Med Res Opin, 30(2), 321-328. https://doi.org/10.1185/03007995.2013.855183 
12. Cenaj, O., Ligon, A. H., Hornick, J. L., & Sholl, L. M. (2019). Detection of ERBB2 Amplification by Next-Generation Sequencing Predicts HER2 Expression in Colorectal Carcinoma. Am J Clin Pathol, 152(1), 97-108. https://doi.org/10.1093/ajcp/aqz031 
13. Cervantes, A., Adam, R., Roselló, S., Arnold, D., Normanno, N., Taïeb, J., Seligmann, J., De Baere, T., Osterlund, P., Yoshino, T., & Martinelli, E. (2023). Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 34(1), 10-32. https://doi.org/10.1016/j.annonc.2022.10.003 
14. Chang, G. J., You, Y. N. Y., Russell, C. A., Tierno, M. B., Turner, M., Bennett, J. P., Lau, A., & Hochster, H. S. (2020). Young-Onset Colon Cancer and Recurrence Risk By Gene Expression. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa019 
15. Chang, X. N., Shang, F. M., Jiang, H. Y., Chen, C., Zhao, Z. Y., Deng, S. H., Fan, J., Dong, X. C., Yang, M., Li, Y., Cai, K. L., Liu, L., Liu, H. L., & Nie, X. (2021). Clinicopathological Features and Prognostic Value of KRAS/NRAS/BRAF Mutations in Colorectal Cancer Patients of Central China. Curr Med Sci, 41(1), 118-126. https://doi.org/10.1007/s11596-021-2326-1 
16. Chaudhari, V. S., & Issa, A. M. (2022). Cost-effectiveness of precision molecular diagnostic tests for stage II colorectal cancer. Ann Transl Med, 10(23), 1260. https://doi.org/10.21037/atm-2022-77 
17. Chiorean, E. G., Nandakumar, G., Fadelu, T., Temin, S., Alarcon-Rozas, A. E., Bejarano, S., Croitoru, A.-E., Grover, S., Lohar, P. V., Odhiambo, A., Park, S. H., Garcia, E. R., Teh, C., Rose, A., Zaki, B., & Chamberlin, M. D. (2020). Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline. JCO Global Oncology(6), 414-438. https://doi.org/10.1200/JGO.19.00367 
18. Clark, J. W., & Sanoff, H. K. (2023, February 28). Systemic chemotherapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach. https://www.uptodate.com/contents/systemic-therapy-for-nonoperable-metastatic-colorectal-cancer-selecting-the-initial-therapeutic-approach
19. Compton, C. (2022). Pathology and prognostic determinants of colorectal cancer - UpToDate. In K. Tanabe (Ed.), UpToDate. https://www.uptodate.com/contents/pathology-and-prognostic-determinants-of-colorectal-cancer?source=machineLearning&search=braf%20colorectal&selectedTitle=6~150&sectionRank=2&anchor=H1022797966#H1022797966 
20. Compton, C. (2023, 05/01/2023). Pathology and prognostic determinants of colorectal cancer. https://www.uptodate.com/contents/pathology-and-prognostic-determinants-of-colorectal-cancer
21. De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G., Kalogeras, K. T., Kotoula, V., Papamichael, D., Laurent-Puig, P., Penault-Llorca, F., Rougier, P., Vincenzi, B., Santini, D., Tonini, G., Cappuzzo, F., Frattini, M., Molinari, F., Saletti, P., . . . Tejpar, S. (2010). 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. Lancet Oncol, 11(8), 753-762. https://doi.org/10.1016/s1470-2045(10)70130-3 
22. Douillard, J. Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., Rivera, F., Kocakova, I., Ruff, P., Blasinska-Morawiec, M., Smakal, M., Canon, J. L., Rother, M., Williams, R., Rong, A., . . . Patterson, S. D. (2013). Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 369(11), 1023-1034. https://doi.org/10.1056/NEJMoa1305275 
23. El-Deiry, W. S., Vijayvergia, N., Xiu, J., Scicchitano, A., Lim, B., Yee, N. S., Harvey, H. A., Gatalica, Z., & Reddy, S. (2015). Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer Biol Ther, 16(12), 1726-1737. https://doi.org/10.1080/15384047.2015.1113356 
24. Fan, J.-Z., Wang, G.-F., Cheng, X.-B., Dong, Z.-H., Chen, X., Deng, Y.-J., & Song, X. (2021). Relationship between mismatch repair protein, RAS, BRAF, PIK3CA gene expression and clinicopathological characteristics in elderly colorectal cancer patients. World journal of clinical cases, 9(11), 2458-2468. https://doi.org/10.12998/wjcc.v9.i11.2458 
25. FDA. (2014). SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED). https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110027B.pdf
26. FDA. (2015). SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED). https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140023B.pdf
27. FDA. (2017). SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED). https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160038B.pdf
28. FDA. (2021). ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA). https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pma&id=454588 
29. Formica, V., Lucchetti, J., Doldo, E., Riondino, S., Morelli, C., Argirò, R., Renzi, N., Nitti, D., Nardecchia, A., Dell'Aquila, E., Ferroni, P., Guadagni, F., Palmieri, G., Orlandi, A., & Roselli, M. (2020). 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. Journal of clinical medicine, 10(1), 87. https://doi.org/10.3390/jcm10010087 
30. Frucht, H., & Lucas, A. L. (2022, January 21). Molecular genetics of colorectal cancer. https://www.uptodate.com/contents/molecular-genetics-of-colorectal-cancer
31. Gray, R. G., Quirke, P., Handley, K., Lopatin, M., Magill, L., Baehner, F. L., Beaumont, C., Clark-Langone, K. M., Yoshizawa, C. N., Lee, M., Watson, D., Shak, S., & Kerr, D. J. (2011). Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol, 29(35), 4611-4619. https://doi.org/10.1200/jco.2010.32.8732 
32. Gunderson, L. L., Jessup, J. M., Sargent, D. J., Greene, F. L., & Stewart, A. K. (2010). Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol, 28(2), 264-271. https://doi.org/10.1200/jco.2009.24.0952 
33. Harris, E. I., Lewin, D. N., Wang, H. L., Lauwers, G. Y., Srivastava, A., Shyr, Y., Shakhtour, B., Revetta, F., & Washington, M. K. (2008). Lymphovascular invasion in colorectal cancer: an interobserver variability study. Am J Surg Pathol, 32(12), 1816-1821. https://doi.org/10.1097/PAS.0b013e3181816083 
34. Jones, J. C., Renfro, L. A., Al-Shamsi, H. O., Schrock, A. B., Rankin, A., Zhang, B. Y., Kasi, P. M., Voss, J. S., Leal, A. D., Sun, J., Ross, J., Ali, S. M., Hubbard, J. M., Kipp, B. R., McWilliams, R. R., Kopetz, S., Wolff, R. A., & Grothey, A. (2017). (Non-V600) BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. J Clin Oncol, 35(23), 2624-2630. https://doi.org/10.1200/jco.2016.71.4394 
35. Kennedy, R. D., Bylesjo, M., Kerr, P., Davison, T., Black, J. M., Kay, E. W., Holt, R. J., Proutski, V., Ahdesmaki, M., Farztdinov, V., Goffard, N., Hey, P., McDyer, F., Mulligan, K., Mussen, J., O'Brien, E., Oliver, G., Walker, S. M., Mulligan, J. M., . . . Harkin, D. P. (2011). Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol, 29(35), 4620-4626. https://doi.org/10.1200/jco.2011.35.4498 
36. Kopetz, S. (2008). Adjuvant Chemotherapy for Stage II Colon Cancer. https://www.cancernetwork.com/colorectal-cancer/adjuvant-chemotherapy-stage-ii-colon-cancer
37. Kopetz, S., Tabernero, J., Rosenberg, R., Jiang, Z. Q., Moreno, V., Bachleitner-Hofmann, T., Lanza, G., Stork-Sloots, L., Maru, D., Simon, I., Capellà, G., & Salazar, R. (2015). Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist, 20(2), 127-133. https://doi.org/10.1634/theoncologist.2014-0325 
38. Loree, J. M., Wang, Y., Syed, M. A., Sorokin, A. V., Coker, O., Xiu, J., Weinberg, B. A., Vanderwalde, A. M., Tesfaye, A., Raymond, V. M., Miron, B., Tarcic, G., Zelichov, O., Broaddus, R. R., Ng, P. K. S., Jeong, K. J., Tsang, Y. H., Mills, G. B., Overman, M. J., . . . Kopetz, S. (2021). Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer. Clinical Cancer Research, 27(16), 4587-4598. https://doi.org/10.1158/1078-0432.Ccr-21-0180 
39. NCCN. (2023a, March 29). NCCN Clinical Practice Guidelines in Oncology; Colon Cancer v1.2023. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
40. NCCN. (2023b, April 25). NCCN Clinical Practice Guidelines in Oncology; Colon Cancer Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
41. O'Connell, M. J., Lavery, I., Yothers, G., Paik, S., Clark-Langone, K. M., Lopatin, M., Watson, D., Baehner, F. L., Shak, S., Baker, J., Cowens, J. W., & Wolmark, N. (2010). Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol, 28(25), 3937-3944. https://doi.org/10.1200/jco.2010.28.9538 
42. Oncotype. (2020a). 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
43. Oncotype. (2020b). Interpreting the Results. https://www.oncotypeiq.com/en-US/colon-cancer/healthcare-professionals/oncotype-dx-colon-recurrence-score/interpreting-the-results
44. Pinheiro, M., Peixoto, A., Rocha, P., Veiga, I., Pinto, C., Santos, C., Pinto, P., Guerra, J., Escudeiro, C., Barbosa, A., Silva, J., & Teixeira, M. R. (2022). 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, 37(4), 895-905. https://doi.org/10.1007/s00384-022-04126-6 
45. Rebersek, M., Mesti, T., Boc, M., & Ocvirk, J. (2019). Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients. Radiol Oncol, 53(1), 85-95. https://doi.org/10.2478/raon-2019-0013 
46. Ribic, C. M., Sargent, D. J., Moore, M. J., Thibodeau, S. N., French, A. J., Goldberg, R. M., Hamilton, S. R., Laurent-Puig, P., Gryfe, R., Shepherd, L. E., Tu, D., Redston, M., & Gallinger, S. (2003). Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med, 349(3), 247-257. https://doi.org/10.1056/NEJMoa022289 
47. Salazar, R., Roepman, P., Capella, G., Moreno, V., Simon, I., Dreezen, C., Lopez-Doriga, A., Santos, C., Marijnen, C., Westerga, J., Bruin, S., Kerr, D., Kuppen, P., van de Velde, C., Morreau, H., Van Velthuysen, L., Glas, A. M., Van't Veer, L. J., & Tollenaar, R. (2011). Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol, 29(1), 17-24. https://doi.org/10.1200/jco.2010.30.1077 
48. Sargent, D. J., Marsoni, S., Monges, G., Thibodeau, S. N., Labianca, R., Hamilton, S. R., French, A. J., Kabat, B., Foster, N. R., Torri, V., Ribic, C., Grothey, A., Moore, M., Zaniboni, A., Seitz, J. F., Sinicrope, F., & Gallinger, S. (2010). Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol, 28(20), 3219-3226. https://doi.org/10.1200/jco.2009.27.1825 
49. Sartore-Bianchi, A., Amatu, A., Porcu, L., Ghezzi, S., Lonardi, S., Leone, F., Bergamo, F., Fenocchio, E., Martinelli, E., Borelli, B., Tosi, F., Racca, P., Valtorta, E., Bonoldi, E., Martino, C., Vaghi, C., Marrapese, G., Ciardiello, F., Zagonel, V., . . . Siena, S. (2019). HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer. Oncologist, 24(10), 1395-1402. https://doi.org/10.1634/theoncologist.2018-0785 
50. Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., Kopetz, S. E., Lieu, C., Lindor, N. M., Minsky, B. D., Monzon, F. A., Sargent, D. J., Singh, V. M., Willis, J., Clark, J., Colasacco, C., Rumble, R. B., Temple-Smolkin, R., Ventura, C. B., & Nowak, J. A. (2017). 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. J Mol Diagn, 19(2), 187-225. https://doi.org/10.1016/j.jmoldx.2016.11.001 
51. Srivastava, G., Renfro, L. A., Behrens, R. J., Lopatin, M., Chao, C., Soori, G. S., Dakhil, S. R., Mowat, R. B., Kuebler, J. P., Kim, G., Mazurczak, M., Lee, M., & Alberts, S. R. (2014). Prospective multicenter study of the impact of oncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer patients. Oncologist, 19(5), 492-497. https://doi.org/10.1634/theoncologist.2013-0401 
52. Therkildsen, C., Bergmann, T. K., Henrichsen-Schnack, T., Ladelund, S., & Nilbert, M. (2014). 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]. https://doi.org/10.3109/0284186X.2014.895036 
53. Venook, A. P., Niedzwiecki, D., Lopatin, M., Ye, X., Lee, M., Friedman, P. N., Frankel, W., Clark-Langone, K., Millward, C., Shak, S., Goldberg, R. M., Mahmoud, N. N., Warren, R. S., Schilsky, R. L., & Bertagnolli, M. M. (2013). Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol, 31(14), 1775-1781. https://doi.org/10.1200/jco.2012.45.1096 
54. Wang, J., Li, S., Liu, Y., Zhang, C., Li, H., & Lai, B. (2020). Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population-based analysis. Cancer Med, 9(1), 361-373. https://doi.org/10.1002/cam4.2673 
55. Xu, Q., Xu, A. T., Zhu, M. M., Tong, J. L., Xu, X. T., & Ran, Z. H. (2013). 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. J Dig Dis, 14(8), 409-416. https://doi.org/10.1111/1751-2980.12063

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