Colorectal (Colon) Cancer

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 both for the individual 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 evaluate Lynch syndrome risk and inform prognosis. Monitoring of serum carcinoembryonic antigen (CEA) is recommended after the resection of most CRCs to detect recurrence. Laboratory testing may also be used to determine whether certain treatments are likely to be effective.

Quick Answers for Clinicians

When is genetic testing for hereditary colorectal cancer syndromes recommended?

Multiple institutions have endorsed laboratory testing via immunohistochemistry (IHC) and, in some cases, microsatellite instability (MSI) testing, in all patients with colorectal and endometrial cancers to determine which patients should receive germline genetic testing for Lynch syndrome or other, less common syndromes associated with colorectal cancer (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). 

When should liquid biopsy tests be used to screen for colorectal cancer?

As of September 2022, there is one U.S. Food and Drug Administration (FDA)-approved blood-based test for colorectal cancer screening: the septin 9 (SEPT9) DNA test. This test is appropriate for individuals who have refused all other screening tests for colorectal cancer. 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
  • Monitor for recurrence
  • Predict response to treatment

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.

Laboratory Tests for CRC Screening for Persons at Average Risk
Test Recommended Frequency Description
Stool-Based Tests (Follow-Up With Visualization Is Required for Positive Test Results)
FIT Yearly

More sensitive than gFOBT

Can be performed with single specimen

FOBT, including gFOBT Yearly

50% of confirmed CRCs have a negative FOBT

In at-risk patients, consider sigmoidoscopy or colonoscopy (even in presence of negative FOBT)

FIT DNA (sDNA-FIT) (testing not performed at ARUP Laboratories)

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
Septin9 (SEPT9) methylated DNA Not yet determined

High negative predictive value

For individuals who refuse other screening tests and are ≥50 yrs of age with average risk and no personal history of polyp removal, CRC, or family history of CRC

Not recommended for routine screening

FDA, U.S. Food and Drug Administration; FIT, fecal immunochemical test; FOBT, fecal occult blood test; gFOBT, guaiac fecal occult blood test; sDNA, stool DNA

Sources: NCCN, 2011  ; Lopes, 2019 ; USPSTF, 2021 

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. 

All polyps removed during screening or surveillance should be examined histologically. Staging is generally performed on the resection specimen using the tumor, node, metastases (TNM) system. Refer to the National Comprehensive Cancer Network (NCCN) guidelines for additional information on staging. 

Molecular Testing

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.

Microsatellite Instability and Mismatch Repair Somatic Testing

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 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. Refer to the Colorectal Cancer - Predictive Testing for Anti-EGFR Therapy Test Fact Sheet for details. 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 KRAS/NRAS somatic 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, including 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, then every 6 months for 3 additional years after surgery. 

Pharmacogenetics​

In addition to the somatic testing for MSI/MMR, BRAF, HER2, and RAS discussed previously (refer to Molecular Testing), certain germline variants 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

Screening for Colorectal Cancer

Note: This is a septin 9 (SEPT9) methylated DNA test

Screening for Lynch Syndrome

For additional information on tests for Lynch syndrome, refer to the ARUP Consult Lynch Syndrome topic and testing algorithm.

Diagnosis of Lynch or Other Hereditary Cancer Syndromes

Includes all four MMR genes known to cause Lynch syndrome

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.

Solid Tumor Prognostic and Treatment Testing

This test does not detect NTRK fusions or HER2 amplification

For additional test information, refer to the Solid Tumor Mutation Panel Test Fact Sheet

Monitoring

Pharmacogenetics

This test does not include all codons recommended as part of extended RAS testing

This test does not include all codons recommended as part of extended RAS testing

Reflex pattern: If the ERBB2 (HercepTest) result is 2+, then ERBB2 (HER2/neu) gene amplification by FISH will be added

References

Additional Resources

Medical Experts

Contributor
Contributor

Leonard

Picture of Nicole Leonard, MD

 

Nicole Leonard, MD
Anatomic and Clinical Pathology Resident, University of Utah School of Medicine and ARUP Laboratories
Contributor

Matynia

Anna P. Matynia, MD
Associate Professor of Pathology (Clinical), University of Utah
Medical Director, Molecular Oncology, ARUP Laboratories