Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer death and the fourth most common form of cancer in the United States. In recent years, both CRC incidence and CRC-related mortality have decreased, which underscores the importance of continued advances in CRC early detection, diagnosis, and care.  Although sporadic colon cancers are more common, hereditary colon cancers are also frequent, and identification of these affects screening recommendations both for the individual and family members. CRC screening strategies rely on imaging, laboratory testing, or a combination of the two. Molecular testing of cancer tissue, including evaluation for microsatellite instability (MSI), is recommended to evaluate for Lynch syndrome (LS) risk and to inform prognosis. Monitoring of serum carcinoembryonic antigen (CEA) is recommended following resection of most CRCs to detect recurrence. Laboratory testing may also be used to determine whether particular treatments are likely to be effective.

Quick Answers for Clinicians

Which hereditary syndromes are associated with colorectal cancer, and when is genetic testing for these syndromes recommended?

Approximately one-fifth of colorectal cancers (CRCs) are related to a hereditary syndrome.  Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer (HNPCC), accounts for 2-4% of colorectal cancer cases in the United States.   Given the frequency of LS, multiple institutions have endorsed immunohistochemistry (IHC) and, in some cases, microsatellite instability (MSI) testing in all colorectal and endometrial cancers to determine which patients should receive germline genetic testing.  Other less common syndromes associated with CRC include familial adenomatous polyposis (FAP), MUTYH (MYH)-associated polyposis (MAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), hereditary diffuse gastric cancer, serrated polyposis syndrome, Cowden syndrome, and Li-Fraumeni syndrome.  If a familial syndrome is suspected, germline genetic testing, such as a hereditary cancer multigene panel, single gene testing, or familial mutation testing, may be appropriate.

Should vitamin D testing be performed in colorectal cancer?

Multiple studies have suggested that a lack of vitamin D is associated with poorer outcomes in colorectal cancer (CRC); however, other studies have indicated no cancer-specific benefit from vitamin D supplementation. Studies are ongoing, but the National Comprehensive Cancer Network (NCCN) does not currently recommend routine vitamin D testing in patients with CRC. 

When should septin9 (SEPT9) methylated DNA testing be used to screen for colorectal cancer?

Septin9 (SEPT9) DNA testing is appropriate in individuals who have refused all other screening tests for colorectal cancer (CRC) and has been FDA approved for this purpose. 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.    Screening may involve visualization (eg, colonoscopy), laboratory testing, or a combination of techniques.

Laboratory Tests for CRC Screening for Persons at Average Riska
Stool-Based Testsb
Test Recommended Frequency   Description
FIT Yearly More accurate than gFOBT

Can be performed with single specimen

FOBT (eg, gFOBT) Yearly 50% of confirmed CRCs have a negative FOBT

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

Positive FOBT requires further evaluation (eg, colonoscopy)

FIT DNA Not yet determined, but every 3 yrs suggested Multitargeted stool-based DNA testing; combines FIT with testing for altered DNA biomarkers in cells shed into stool

Reasonable alternative to other stool-based and visualization-based tests 

Greater single-test sensitivity for detecting CRC compared with FIT alone

Serum Test
Test Recommended Frequency Description
Septin9 (SEPT9) methylated DNA Not yet determined Biomarker for presence of CRC; high negative predictive value

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

Not recommended for routine screening

aAverage risk as defined by ACS: no history of adenoma or IBD; negative family history (having neither first-degree nor second-degree relatives with CRC, nor a clustering of LS-related cancers in the family, and no history of abdominal or pelvic radiation). High-risk patients may require more frequent testing, based on personal or family history of CRC, adenomatous polyp, IBD, or other heritable CRC syndrome; history of abdominal or pelvic radiation.

bPositive tests require follow-up with direct visualization (eg, colonoscopy)

ACS, American Cancer Society; ASCO, American Society of Clinical Oncology; FIT, fecal immunochemical test; FOBT, fecal occult blood test; gFOBT, guaiac fecal occult blood test; IBD, inflammatory bowel disease; NCCN, National  Comprehensive Cancer Network

Sources: NCCN, 2019  ; Lopes, 2019 

Diagnosis

Initial Workup

The initial laboratory workup for CRC appropriate for resection includes a CBC, chemistry profile, and CEA baseline measurement. 

The initial laboratory workup in patients with suspected metastatic synchronous adenocarcinoma includes a CBC, chemistry profile, and CEA measurement.  Tumor KRAS/NRAS testing is also recommended, and BRAF testing should be considered (see RAS Somatic Testing and BRAF Somatic Testing, below). 

Histopathology

All polyps removed should be examined histologically. Cancer staging is generally performed via the tumor, node, metastases (TNM) system following surgical exploration and pathologic examination. 

Molecular Testing

Tissue from a primary, recurrent, or metastatic colorectal tumor is acceptable for somatic molecular testing because results are similar for 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 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 for mismatch repair (MMR) protein status via immunohistochemistry (IHC), is recommended in all patients with a history of CRC to evaluate for LS risk. MSI (either low or high) or MMR deficiency identifies patients at high risk.  See the Lynch Syndrome ARUP Consult topic for more information.

MSI testing is also useful to determine whether to use adjuvant chemotherapy in stage II disease, and both MSI and MMR testing are useful in treatment selection in stage IV disease.  High MSI and MMR deficiency are both associated with a more favorable prognosis in stage II disease and decreased likelihood of metastases. 

Extended RAS Somatic Testing

Extended RAS gene testing, specifically KRAS (codons 12 and 13 of exon 2; codons 59 and 61 of exon 3; and codons 117 and 146 of exon 4) and NRAS (codons 12 and 13 of exon 2; codons 59 and 61 of exon 3; and codons 117 and 146 of exon 4), is recommended in all patients with CRC at the diagnosis of stage IV disease  or being considered for anti-EGFR therapy. Patients with any known KRAS variant in exons 2, 3, or 4 or NRAS variant in exons 2, 3, or 4 should not receive cetuximab or panitumumab.  No specific methodology is recommended for RAS testing.  Wild-type KRAS is associated with improved prognosis and increased lymph node retrieval. 

BRAF Somatic Testing

BRAF testing is recommended in all patients with metastatic CRC at the diagnosis of stage IV disease and should be considered in patients with wild-type KRAS/NRAS metastatic colon cancer.  Wild-type BRAF is associated with improved prognosis and increased lymph node retrieval.  Presence of the BRAF V600E variant in patients with MMR-deficient CRC tumors with loss of MLH1 suggests sporadic CRC, although it does not rule out Lynch syndrome. Presence of the BRAF V600E variant also decreases the probability that treatment with panitumumab or cetuximab therapy will be effective without anti-BRAF therapy (eg, vemurafenib); combination therapy is recommended.  See the NCCN guidelines  for specific regimens.

Monitoring

Careful long-term monitoring is recommended following treatment to assess for complications or recurrence.  Recommended monitoring includes a combination of imaging (eg, colonoscopy), clinical assessment, and laboratory testing.

Carcinoembryonic Antigen

Laboratory test-based monitoring in CRC includes serum CEA. CEA should be regularly monitored for changes in concentration from a preoperative baseline. A serially elevated postoperative titer suggests recurrence and requires examination.  Stage II, III, and IV tumors warrant measurement of CEA every 3-6 months for 2 years after surgery, then every 6 months for a total of 5 years.   Routine CEA measurements are not recommended beyond 5 years because most recurrences take place within 5 years of treatment.  Follow-up for an elevated CEA should include imaging and clinical assessment until CEA levels stabilize or disease is discovered. 

Pharmacogenetics​

Fluorouracil Drugs

MSI-low (MSI-L) or microsatellite stable (MSS) tumors are associated with improved outcomes with 5-fluorouracil (5-FU) adjuvant therapy.  Patients with low-risk stage II MSI-high (MSI-H) tumors should not be given 5-FU adjuvant therapy.  For more information and guidelines on testing for 5-FU sensitivity, see the Germline Pharmacogenetics ARUP Consult topic.

Irinotecan​

Decreased UGT1A1 gene expression may lead to drug toxicity, including development of severe neutropenia, from irinotecan.  The UGT1A1*28 allele is associated with an increased risk of toxicity.  Patients who are heterozygous or homozygous for the *28 allele should receive a reduced starting dose of irinotecan  and be treated with caution. Pretreatment testing for UGT1A1*28 should be considered, although guidelines have yet to be established.  For additional information and guidelines on UGT1A1 testing, see the Germline Pharmacogenetics ARUP Consult topic.

Fluoropyrimidine​

MSI-H status and MMR deficiency are associated with a decreased benefit from fluoropyrimidine adjuvant therapy in stage II disease.  Certain variants in the dihydropyrimidine dehydrogenase gene (DYPD) are associated with life-threatening toxicity from 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. 

Anti-EGFR Therapy

As mentioned above, patients with any known KRAS variant in exon 2, 3, or 4 or NRAS variant in exon 2, 3, or 4 should not receive cetuximab or panitumumab, and presence of the BRAF V600E variant also decreases the probability that treatment with these drugs will be effective without anti-BRAF therapy.  Appropriate treatment regimens are detailed in the NCCN guidelines.  HER2 overexpression may also predict resistance to anti-EGFR treatment.  However, HER2 testing is not currently recommended for treatment planning. 

ARUP Lab Tests

Screening for Colorectal Cancer

General Screening

Screen for CRC

Screen adults of either sex, ≥50 years of age, who have been offered and declined other recommended screening tests

Note: This is a septin9 (SEPT9) methylated DNA test

Screening for Lynch Syndrome

Screening test for LS

Preferred screening test for LS in individuals with CRC

Do not use in endometrial cancer

For additional information on tests for LS, see the Lynch Syndrome ARUP Consult topic and testing algorithm.

Diagnosis of Lynch or Other Hereditary Cancer Syndromes

Recommended test to confirm a diagnosis of hereditary gastrointestinal (GI) cancer in individuals with a personal or family history of GI cancer and/or polyposis when a familial variant is unknown

Includes all four MMR genes known to cause LS

Recommended test to confirm diagnosis of hereditary cancer syndrome in individuals with personal or family history consistent with features of more than one cancer syndrome

Useful when a pathogenic familial variant identifiable by sequencing is known

For more information about diagnostic testing for LS, including specific MMR gene testing, see the Lynch Syndrome ARUP consult topic and testing algorithm.

Solid Tumor Prognostic and Treatment Testing

Assess for targeted variants that are useful for prognosis and/or treatment of individuals with solid tumor cancers

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

Monitoring

Monitor patient for tumor recurrence

Pharmacogenetics

Determine eligibility for anti-EGFR (cetuximab and panitumumab) therapy in patients with metastatic CRC

Does not include all codons recommended as part of extended RAS testing

Predict response to anti-EGFR and MAPK pathway therapies in a variety of malignancies, including CRC

Does not include all codons recommended as part of extended RAS testing

Detect activating BRAF mutations at codon 600, which can indicate resistance to anti-EGFR therapy in CRC

Also used within LS reflex testing pathway (for CRC specimens only)

Determine BRAF V600E mutation status in patients with solid tumors to select candidates for targeted therapy with kinase (BRAF and/or MEK) inhibitors; monitor response to therapy and disease progression in patients carrying BRAF V600E mutation

Predict response to anti-EGFR and MAPK pathway therapies in a variety of malignancies, including CRCs; detect activating NRAS mutations associated with relative resistance to anti-EGFR therapy 

Does not include all codons recommended as part of extended RAS testing

Predict risk of dose-related toxicity to 5-FU therapy

Use for dosage planning for individuals who will receive high-dose irinotecan (>150 mg/m2), have personal or family history of sensitivity to irinotecan, or have experienced neutropenia while receiving irinotecan

Medical Experts

Contributor
Contributor

Matynia

Anna P. Matynia, MD
Assistant Professor of Clinical Pathology, University of Utah
Section Chief, Molecular Genetics and Genomics; Medical Director, Molecular Oncology, ARUP Laboratories
Contributor

References

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