Description:
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:

1. Tumor tissue genotyping for KRAS, NRAS and BRAF mutations is considered MEDICALLY NECESSARY for all patients with metastatic colorectal cancer.
2. Testing for KRAS mutation (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF V600 mutations  is considered MEDICALLY NECESSARY prior to deciding treatment with cetuximab or panitumumab.
3. Testing for KRAS, NRAS and BRAF mutations in all other situations not described above 

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 a patient’s illness.

3. Testing for KRAS, NRAS and BRAF mutations in all other situations not described above and therefore considered NOT MEDICALLY NECESSARY. 

NOTE: For 5 or more 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 CAM 204115.

Table of Terminology

Rationale 
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States following lung cancer. The American Cancer Society (ACS) estimates 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer for 2022. Overall, the lifetime risk of developing colorectal cancer is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women (ACS, 2022). 

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, Bergmann, Henrichsen-Schnack, Ladelund, & Nilbert, 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 & Grothey, 2022). 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 & Grothey, 2022). 

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).

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, Ligon, Hornick, & Sholl, 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). 22 studies including 2395 patients 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. 154 patients were included, 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, Mesti, Boc, & Ocvirk, 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).

Food and Drug Administration (FDA) 
As per FDA requirements, the Erbitux (cetuximab) package insert (FDA, 2012) indicates that the drug is to be used for “K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer as determined by FDA-approved tests.” Similarly, the Vectibix (panitumumab) package insert (FDA, 2009) states that “Use of Vectibix is not recommended for the treatment of colorectal cancer with these [KRAS] mutations” (FDA, 2009, 2012).

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).

National Comprehensive Cancer Network (NCCN)
The guidelines v.2.2022 recommend that “all patients with metastatic colorectal cancer should have tumor tissue 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, 4) or NRAS mutation (exon 2, 3, 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. HER2-targeted therapies are now recommended in patients with HER2 overexpression. Therefore, the NCCN now recommends testing for HER2 amplifications in patients with metastatic CRC. However, HER2 testing is not required in patients with known KRAS/NRAS or BRAF mutations, and the NCCN states that anti HER2 therapy is only indicated in HER2-positive tumors that are also RAS and BRAF wild-type (NCCN, 2022).

Routine EGFR testing is not recommended (NCCN, 2022). 

Overall, the NCCN states that “determination of tumor gene status for KRAS/RAS and BRAF mutations, as well as HER2 amplifications and MSI/MMR [microsatellite instability/mismatch repair] status (if not previously done), are recommended for patients with mCRC” (NCCN, 2022).

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG)
The EWG determined that, “for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy” (EGAPP, 2013). However, the EWG “found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario,” and “the level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low” (EGAPP, 2013).

European Society for Medical Oncology (ESMO)
ESMO states that RAS mutational testing should be done at the time of diagnosing metastatic CRC and that RAS testing is mandatory before treatment with cetuximab and panitumumab. ESMO notes that RAS analysis should include “at least KRAS exons 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117)”. ESMO also recommends that BRAF mutational status be assessed alongside RAS (Van Cutsem et al., 2016).

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).

National Institute for Health and Care Excellence (NICE)
NICE recommends testing for RAS and BRAF V600E mutations in all people with metastatic colorectal cancer suitable for systemic anti-cancer treatment (NICE, 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).

References: 

1. ACS. (2022). Key Statistics for Colorectal Cancer. Retrieved from https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html#:~:text=Overall%2C%20the%20lifetime%20risk%20of,risk%20for%20developing%20colorectal%20cancer.
2. Allegra, C. J., Jessup, J. M., Somerfield, M. R., Hamilton, S. R., Hammond, E. H., Hayes, D. 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. doi:10.1200/jco.2009.21.9170
3. 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. doi:10.1200/jco.2015.63.9674
4. Argilés, G., Tabernero, J., Labianca, R., Hochhauser, D., Salazar, R., Iveson, T., . . . Arnold, D. (2020). Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 31(10), 1291-1305. doi:10.1016/j.annonc.2020.06.022
5. ASCO. Retrieved from https://www.asco.org/research-guidelines/quality-guidelines/guidelines/gastrointestinal-cancer#/9766
6. 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. doi:10.1093/ajcp/aqz031
7. Chang, X. N., Shang, F. M., Jiang, H. Y., Chen, C., Zhao, Z. Y., Deng, S. H., . . . 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. doi:10.1007/s11596-021-2326-1
8. Chiorean, E. G., Nandakumar, G., Fadelu, T., Temin, S., Alarcon-Rozas, A. E., Bejarano, S., . . . Chamberlin, M. D. (2020). Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline. JCO Global Oncology(6), 414-438. doi:10.1200/JGO.19.00367
9. Clark, J. W., & Grothey, A. (2022, April 14). Systemic chemotherapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach. Retrieved from https://www.uptodate.com/contents/systemic-therapy-for-nonoperable-metastatic-colorectal-cancer-selecting-the-initial-therapeutic-approach
10. Compton, C. (2022). Pathology and prognostic determinants of colorectal cancer - UpToDate. In K. Tanabe (Ed.), UpToDate. Waltham. MA.
11. De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G., . . . 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. doi:10.1016/s1470-2045(10)70130-3
12. Douillard, J. Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., . . . Patterson, S. D. (2013). Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 369(11), 1023-1034. doi:10.1056/NEJMoa1305275
13. EGAPP. (2013). Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med, 15(7), 517-527. doi:10.1038/gim.2012.184
14. 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. doi:10.12998/wjcc.v9.i11.2458
15. FDA. (2009). Vectibix Package Insert. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125147s080lbl.pdf
16. FDA. (2012). Erbitux Package Insert. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125084s225lbl.pdf
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18. FDA. (2015). SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED). Retrieved from https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140023B.pdf
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20. FDA. (2021). ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA). Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pma&id=454588
21. Formica, V., Lucchetti, J., Doldo, E., Riondino, S., Morelli, C., Argirò, R., . . . 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. doi:10.3390/jcm10010087
22. Frucht, H., & Lucas, A. L. (2022, January 21). Molecular genetics of colorectal cancer. UpToDate. Retrieved from https://www.uptodate.com/contents/molecular-genetics-of-colorectal-cancer
23. Jones, J. C., Renfro, L. A., Al-Shamsi, H. O., Schrock, A. B., Rankin, A., Zhang, B. Y., . . . Grothey, A. (2017). (Non-V600) BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. J Clin Oncol, 35(23), 2624-2630. doi:10.1200/jco.2016.71.4394
24. Loree, J. M., Wang, Y., Syed, M. A., Sorokin, A. V., Coker, O., Xiu, J., . . . Kopetz, S. (2021). Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer. Clinical Cancer Research, 27(16), 4587-4598. doi:10.1158/1078-0432.Ccr-21-0180
25. NCCN. (2022, January 21). NCCN Clinical Practice Guidelines in Oncology; Colon Cancer v2.2022. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
26. NICE. (2020). Colorectal cancer. Retrieved from https://www.nice.org.uk/guidance/ng151/chapter/Recommendations#molecular-biomarkers-to-guide-systemic-anti-cancer-therapy
27. Pinheiro, M., Peixoto, A., Rocha, P., Veiga, I., Pinto, C., Santos, C., . . . 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. doi:10.1007/s00384-022-04126-6
28. 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. doi:10.2478/raon-2019-0013
29. Sartore-Bianchi, A., Amatu, A., Porcu, L., Ghezzi, S., Lonardi, S., Leone, F., . . . Siena, S. (2019). HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer. Oncologist, 24(10), 1395-1402. doi:10.1634/theoncologist.2018-0785
30. Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., . . . 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. doi:10.1016/j.jmoldx.2016.11.001
31. 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. doi:10.3109/0284186X.2014.895036
32. Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., . . . Arnold, D. (2016). ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol, 27(8), 1386-1422. doi:10.1093/annonc/mdw235
33. 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. doi:10.1111/1751-2980.12063

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