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Leonard
Matynia
Colorectal cancer (CRC), also referred to as colon cancer, is a leading cause of cancer death. Although sporadic colon cancers are more common, hereditary colon cancers also occur, and the identification of these cancers influences screening recommendations for both patients and their family members. CRC screening strategies rely on colonoscopy findings, laboratory test results, or a combination of the two. Molecular testing of cancer tissue, including evaluation for microsatellite instability (MSI), is recommended to inform prognosis, guide therapy, and determine the need for a patient’s family members to be tested for Lynch syndrome. Monitoring of serum carcinoembryonic antigen (CEA) is recommended after the resection of most CRCs to detect recurrence.
Quick Answers for Clinicians
Multiple institutions have endorsed somatic genetic testing in all patients with colorectal cancer (CRC) and endometrial cancer to determine which patients should receive germline genetic testing for Lynch syndrome or other, less common syndromes associated with CRC (eg, familial adenomatous polyposis, MUTYH [MYH]-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, hereditary diffuse gastric cancer, serrated polyposis syndrome, Cowden syndrome, and Li-Fraumeni syndrome).
As of May 2024, there is one FDA-approved blood-based test for colorectal cancer (CRC) screening: the septin 9 (SEPT9) DNA test. This test is appropriate for individuals who have a history of not completing other screening tests for CRC. It is not recommended for routine screening, and the appropriate repeat testing interval has not been determined.
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.
| Test | Recommended Frequency | Description |
|---|---|---|
| Stool-Based Tests (Follow-Up With Visualization Is Required for Positive Test Results) | ||
| FIT | Yearly | More sensitive and specific than guaiac fecal occult blood test Can be performed with single specimen |
| FIT DNA (sDNA-FIT) | Every 1-3 yrs (every 3 yrs is suggested and approved by the FDA; every 1-3 yrs is suggested by the USPSTF) | Combines FIT with testing for altered DNA biomarkers in cells shed into the stool Greater single-test sensitivity than FIT alone |
| Serum Test | ||
| SEPT9 methylated DNA | Not yet determined | High negative predictive value For individuals who have been offered and have a history of not completing other screening tests, are ≥50 yrs of age with average risk, and have no personal history of polyp removal or CRC and no family history of CRC Not recommended for routine screening |
FIT, fecal immunochemical test; SEPT9, septin 9; sDNA, stool DNA | ||
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.
ARUP Laboratory Tests
Massively Parallel Sequencing
Qualitative Immunoassay
Capillary Electrophoresis/Polymerase Chain Reaction (PCR)
Qualitative Immunohistochemistry (IHC)/Qualitative Real-Time Polymerase Chain Reaction
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-dependent Probe Amplification
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Includes all four MMR genes known to cause Lynch syndrome
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-dependent Probe Amplification
For additional test information, refer to the Hereditary Gastric Cancer Panel, Sequencing and Deletion/Duplication Test Fact Sheet
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Massively Parallel Sequencing
For more information about diagnostic testing for Lynch syndrome, including specific MMR gene testing, refer to the ARUP Consult Lynch Syndrome topic and testing algorithm.
Massively Parallel Sequencing
This test does not detect NTRK fusions or HER2 amplification
For additional test information, refer to the Solid Tumor Mutation Panel Test Fact Sheet
Quantitative Electrochemiluminescent Immunoassay
Polymerase Chain Reaction/Pyrosequencing
This test does not include all codons recommended as part of extended RAS testing
Massively Parallel Sequencing
Polymerase Chain Reaction (PCR)
Immunohistochemistry (IHC)
Reflex pattern: If the ERBB2 (HercepTest) result is 2+, then ERBB2 (HER2/neu) gene amplification by FISH will be added
Fluorescence in situ Hybridization (FISH)
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring/Fragment Analysis
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
Polymerase Chain Reaction (PCR)/Fragment Analysis
References
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NCCN - colon cancer v2.2024
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: colon cancer. Version 2.2024. Updated Apr 2024; accessed Apr 2024.
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NCCN - genetic/familial high-risk assessment—colorectal v2.2023
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: genetic/familial high-risk assessment—colorectal. Version 2.2023. Updated Oct 2023; accessed Apr 2024.
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NCCN - colorectal cancer screening v1.2024
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: colorectal cancer screening. Version 1.2024. Updated Feb 2024; accessed Apr 2024.
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30802159
Lopes G, Stern MC, Temin S, et al. Early detection for colorectal cancer: ASCO resource-stratified guideline. J Glob Oncol. 2019;5:1-22.
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34003218
US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement [published correction appears in JAMA. 2021;326(8):773]. JAMA. 2021;325(19):1965-1977.
For additional information on tests for Lynch syndrome, refer to the ARUP Consult Lynch Syndrome topic and testing algorithm.