Colorectal (Colon) Cancer

Indications for Testing

Laboratory testing for CRC is used to:

• Screen average-risk individuals
• Diagnose and inform prognosis in patients with suggestive signs and symptoms or a family history of CRC
• Predict response to treatment
• Monitor for recurrence

Laboratory Testing

Screening

Screening recommendations for CRC vary. ^, ,  Most guidelines recommend regular CRC screening for individuals 50-75 years of age. ^,  The U.S. Preventive Services Task Force (USPSTF) also has a B-grade recommendation for screening in individuals 45-49 years of age, and a C-grade recommendation for selective screening in individuals 76-85 years of age.  Screening may involve imaging (eg, colonoscopy), laboratory testing, or a combination of techniques.

Diagnosis and Prognosis

Initial Workup

The initial laboratory workup for patients with resectable CRC includes a CEA baseline measurement, CBC, and chemistry profile. 

The initial laboratory workup in patients with suspected metastatic synchronous adenocarcinoma also includes a CEA measurement, CBC, and chemistry profile.  Additionally, tumor KRAS/NRAS testing and BRAF testing are recommended. 

Testing for Somatic Variants

Tissue from a primary, recurrent, or metastatic colorectal tumor is acceptable for somatic molecular testing because results are similar for all of these specimen types.  Formalin-fixed, paraffin-embedded tissue should be used. 

Germline genetic testing for hereditary CRC syndromes should be based on clinical presentation and family history, and this testing should be performed in conjunction with genetic consultation.  A hereditary cancer multigene panel, single gene testing, or familial mutation testing may be appropriate if a hereditary cancer is suspected.

Testing for MSI via polymerase chain reaction (PCR) or testing for mismatch repair (MMR) protein status via immunohistochemistry (IHC) is recommended in all patients with a history of CRC to evaluate for Lynch syndrome risk.  Refer to the ARUP Consult Lynch Syndrome topic for more information.

MSI testing is also useful for treatment planning in stage II disease. Both MSI and MMR testing are useful for prognosis and to guide treatment selection in stage IV disease. 

Other Molecular Testing

BRAF testing and extended RAS gene testing (KRAS and NRAS) are recommended in all patients with CRC who have been diagnosed with metastatic disease  because BRAF, KRAS, and NRAS variants are associated with resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. BRAF testing is also indicated in screening for Lynch syndrome because the presence of the BRAF V600E variant suggests that CRC is likely sporadic (ie, unrelated to Lynch syndrome).

Testing for HER2 amplification is useful in treatment planning and is recommended in patients with metastatic CRC, unless there is a known BRAF or RAS variant.  HER2 amplification can be detected by IHC, fluorescence in situ hybridization (FISH), or next generation sequencing (NGS) testing; an NGS panel may be particularly useful to detect HER2 amplification in conjunction with other biomarkers. 

Testing for NTRK fusions, which are very rare, may be considered in metastatic MMR-deficient CRC tumors that are wild type for BRAF, KRAS, and NRAS. Tumors with NTRK fusions may be sensitive to NTRK inhibitors. 

Monitoring

Careful long-term monitoring that includes a combination of colonoscopy, clinical assessment, and laboratory testing is recommended following CRC treatment to assess for complications or recurrence. 

Serum CEA should be regularly monitored after surgery. A serial increase in CEA from a preoperative baseline suggests recurrence and requires further examination (ie, imaging and clinical assessment).  For stage II, III, and IV tumors, CEA should be measured every 3-6 months for 2 years, and then every 6 months for 5 additional years after surgery. 

Pharmacogenetics​

In addition to the somatic testing for MSI/MMR and BRAF, HER2, and RAS variants discussed previously (refer to the Testing for Somatic Variants and the Other Molecular Testing sections), clinicians may choose to order testing for certain germline variants that have therapeutic implications.

UGT1A1

Decreased UGT1A1 gene expression and the UGT1A1*28 allele are associated with an increased risk of toxicity with irinotecan treatment.  Testing for UGT1A1*28 should be considered before irinotecan treatment.  For additional information on UGT1A1 testing, refer to the ARUP Consult Germline Pharmacogenetics topic.

DPYD

Certain dihydropyrimidine dehydrogenase (DPYD) gene variants are associated with life-threatening toxicity as a result of treatment with fluoropyrimidine.  These variants are thought to occur in 1-2% of the population; however, universal testing for these variants before fluoropyrimidine treatment is not currently recommended.  For additional information on DPYD testing, refer to the ARUP Consult Germline Pharmacogenetics topic.