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Colorectal Cancer: Laboratory Support of Diagnosis and Management

Colorectal Cancer: Laboratory Support of Diagnosis and Management

Clinical Focus

Colorectal Cancer

Laboratory Support of Diagnosis and Management

  

Contents:

Clinical Background  - Table 1

Individuals Suitable for Testing  - Table 2  - Table 3

Test Availability  -  Table 4

Test Selection and Interpretation  - Table 5  - Figure 1  -  Figure 2

References
 

Clinical Background [return to contents]

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with projections of 50,800 deaths and 142,800 newly diagnosed cases in 2013.1 There are several types of CRC: sporadic, familial, and inherited (Table 1). Sporadic cases are the most common and apparently result from environmental factors, diet, and aging. Familial CRC is not well understood but is characterized by increased risk of CRC and an unclear pattern of inheritance. Inherited CRC, on the other hand, exhibits a clear pattern of inheritance. Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of inherited CRC. Click here for a more detailed discussion of Lynch syndrome. Familial adenomatous polyposis (FAP), an autosomal dominant disorder, is characterized clinically by the presence of hundreds to thousands of colorectal polyps identified at an early age (<30 years). FAP will progress to colon cancer unless colectomy is performed. It is also associated with an increased lifetime risk of other cancers, including duodenal cancer (5% to 11% risk).

Table 1. Probability of Developing Colorectal Cancer2,3

Etiology Probability of Developing CRC

% of New

CRC Cases

Sporadic CRCa 4% by age 79 75
Familial CRCb

1 first-degree relative with CRC: 9% by age 79

More than 1 first-degree relative with CRC: 16% by age 79

1 first-degree relative with CRC before age 45: 15% by age 79

1 first-degree relative with colorectal adenoma: 8% by age 79

15 to 20

 

Hereditary CRC

Lynch syndrome

80% by age 75 5

FAP

90% by age 45 1

Other

Attenuated FAP: 69% by age 80

MYH-associated neoplasia: unknown

Peutz-Jeghers syndrome: 39% by age 64

Juvenile polyposis syndrome: 17% to 68% by age 60

Rare

 

CRC, colorectal cancer; FAP, familial adenomatous polyposis.
a Probability refers to general population.

b Probabilities refer to individuals diagnosed with the indicated clinical syndrome.

Individuals Suitable for Testing [return to contents]

  • Individuals recommended for CRC screening (Table 2)

  • Individuals with CRC who meet any of the Bethesda criteria (Table 3)

  • Individuals with diagnosed CRC

  • Family members of individuals with inherited CRC

Table 2. Colorectal Cancer Screening Recommendations4,5

Population Screening Options Age to Begin Screening

Average-risk men and women

Cancer Prevention Tests

  • Colonoscopy every 10 yearsa

  • Flexible sigmoidoscopy every
    5 to 10 years

  • CT colonography every 5 years

  • DCBE every 5 years

Cancer Detection Tests

  • Annual FITb

  • Annual g-FOBT, high sensitivity

50 years

45 years for African Americans

First-degree relative of an individual with CRC or
advanced adenoma at age
60 years

Same as for those with average
risk

40 years

 1 first-degree relative with CRC or advanced adenoma at age
<60 years, or 2 first-degree relatives with CRC or advanced adenoma

Colonoscopy every 5 years

40 years or 10 years younger than the earliest diagnosis in the family, whichever comes first

High risk for Lynch syndrome (first-degree relative with Lynch syndrome or carrier of known MMR gene mutation)

Colonoscopy every 2 years

20 to 25 years until age 40 years, then annually

High risk for FAP (first-degree relative with FAP or carrier of known APC gene mutation)

Annual sigmoidoscopy or colonoscopy

10 to 12 years

CT, computed tomography; DCBE, double contrast barium enema; FIT, fecal immunochemical test; gFOBT, guaiac-based fecal occult blood test; CRC, colorectal cancer; MMR, mismatch repair; FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli gene.
a Colonoscopy is recommended by the American College of Gastroenterology as the preferred CRC screening test.4
b FIT is recommended by the American College of Gastroenterology as the preferred test for patients who decline all cancer prevention tests.4

Table 3. Bethesda Guidelines for Testing Colorectal Tumors for MSI6

Colorectal tumors should be tested for MSI in individuals meeting any of the following:

  • CRC diagnosed at age <50 years

  • Presence of synchronous CRC (multiple CRCs 6 months after initial tumor removal), metachronous CRC (CRC recurrence >6 months after initial tumor removal), or other HNPCC-associated tumorsa

  • CRC with the MSI-H histologyb diagnosed at age <60 years

  • CRC in 1 first-degree relative with an HNPCC-related tumor with 1 of the cancers diagnosed at age <50 years

  • CRC diagnosed in 2 first- or second-degree relatives with HNPCC-related tumors

a Endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.

b Presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.

Test Availability [return to contents]

Table 4 lists tests used to assess risk, screen, diagnose, determine prognosis, select therapy, and monitor CRC. This table is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

Additional tests that are available for diagnosis and management of Lynch Syndrome can be found here.

Table 4. Tests Available for Screening, Diagnosis and Management of Colorectal Cancer

Test Code Assay Method Description

Clinical Use

Screen for CRC

 

 

11290Z Fecal Globin, by Immunochemistry
(InSure®)
Fecal immunochemistry test targeting globin portion of hemoglobin; colorimetric detection

Screen for lower GI bleeding associated with CRC, adenomas, polyps, and other lower GI conditions

16983 ColoVantage®
(Methylated Septin 9)a
Real-time PCR of SEPT9
gene

Aid in the detection of CRC in patients non-adherent to current screening guidelines

Diagnose CRC

 

 

14517 Tissue, Gastrointestinal Pathology Report Hematoxylin and eosin stain; microscopy Diagnose CRC
 
14989X Lynch Syndrome, Microsatellite Instability
(MSI)a
Multiplex PCR amplification
of 5 NCI-recommended microsatellites; fluorescent fragment analysis

Differential diagnosis of CRC; assess risk of Lynch syndrome in patients with CRC

Confirmatory Lynch syndrome tests are offered; assistance in test selection is available from our Genetic Counselors (1-866-GENE-INFO).

91332 Lynch Syndrome Tumor
Panel, IHCb
Immunohistochemical
analysis for MLH1, MSH2,
MSH6, and PMS2 proteins
16930 APC Gene Deletion or Duplicationa Semi-quantitative fluorescent PCR Diagnose familial adenomatous polyposis (FAP)
16934 APC Gene Sequencinga PCR amplification and DNA sequencing

Determine Prognosis

16811

CellSearch® Circulating Tumor Cells, Colon

Immunomagnetic enrichment
of epithelial cells; counting of cells labeled with fluorescent monoclonal antibodies
Predict progression-free and overall survival in patients with stage IV colorectal carcinoma
91426 Chromosomal Microarray, Oncology, ClariSure® Oligo-SNP, FFPE Oligo-SNP array Assess prognosis in patients with CRC
14603X Chromosome Analysis,
Solid Tumor
Culture, karyotype
36158X DNA Cell Cycle Analysis, Paraffin Block Flow cytometry Predict overall survival in patients with CRC
36162X p53 Oncoprotein, IHC with Interpretation Immunohistochemical
assay
Predict recurrence-free survival in patients with CRC

Select Therapy

18902 Colorectal Cancer Mutation Panel (KRAS, PIK3CA,
BRAF, NRAS)a,b
PCR amplification and DNA sequencing for KRAS, PIK3CA,BRAF, and NRAS Predict response to EGFR-targeted immunotherapy in patients with metastatic CRC
16510 KRAS Mutation Analysisa PCR amplification of
codons 12, 13, and 61; DNA
sequencing
Determine suitability for EGFR-targeted immunotherapy
14989X Lynch Syndrome,
Microsatellite Instability
(MSI)a
Multiplex PCR amplification
of 5 NCI-recommended microsatellites; fluorescent fragment analysis
Predict response to single-agent fluoropyrimidine therapy in stage II CRC patients
17813X UGT1A1 Gene Polymorphism (TA
Repeat)a
PCR amplification of
promoter region of UGT1A1; fluorescent detection
Predict irinotecan toxicity; assist in selecting initial dosage for patients with metastatic or recurrent CRC

Monitor CRC

978X Carcinoembryonic Antigen (CEA) Immunochemiluminometric assay Monitor therapeutic response; detect residual disease, detect recurrence

GI, gastrointestinal; CRC, colorectal cancer; FFPE, formalin-fixed paraffin-embedded tissue; NCI, National Cancer Institute.
a This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.
b Components of panels can be ordered individually. For test codes and ordering information, refer to the Directory of Services or the online Test Center.

Test Selection and Interpretation [return to contents]

Screening
The American College of Gastroenterology (ACG)4 and others 5 recommend screening average-risk individuals with one of several options (Table 2). These options can be broadly categorized into cancer prevention tests, which can detect cancer and (precancerous) adenomatous polyps, and cancer detection tests. Detection tests are not good at detecting polyps and usually have a lower sensitivity than the prevention tests.

Colonoscopy
The ACG’s preferred screening option is colonoscopy because of its sensitivity and ability to detect as well as treat precancerous lesions.4 Colonoscopy is also required for follow-up of positive screening results from nonendoscopic tests.

Fecal Immunochemical Test (FIT)
When a patient declines a cancer prevention test, the ACG recommends offering a cancer detection test. Among the cancer detection tests, the ACG prefers the fecal immunochemical test (FIT).4

Relative to guaiac-based tests for occult blood, the InSure® FIT is less subject to interfering materials and consequently does not require the dietary and medication restrictions that are required for guaiac-based testing. Additionally, the brush-sampling technique used for the InSure FIT improves participation in occult blood testing.7 FIT is more specific for occult bleeding in the colon and rectum, thus making it less likely that bleeding is from the upper gastrointestinal tract associated with ulcers.8 Newer guaiac-based tests have improved sensitivity relative to older versions. However, the ACG still prefers FIT because of a greater weight of evidence and better adherence relative to guaiac-based tests.4

Positive FIT results generally reflect the presence of blood in the stool and may be associated with CRC. The ACG recommends that positive FIT results be followed up with colonoscopy; flexible sigmoidoscopy or repeat testing is not indicated. Negative FIT results do not rule out CRC; false-negative results can occur because of uneven distribution of blood in the feces or intermittent bleeding.

ColoVantage® (methylated Septin 9)
The ColoVantage® (methylated Septin 9) assay has the advantage of being a plasma-based test that requires no patient preparation. A physician may order the ColoVantage test for screen-eligible patients who have previously avoided established CRC screening methods such as colonoscopy and FITs. ColoVantage is not a replacement test for colonoscopy.

The ColoVantage test detects methylated DNA from the SEPT9 gene in plasma. A case-control study performed at Quest Diagnostics showed that the ColoVantage test is 70% sensitive for CRC detection at a specificity of 89%.9 ColoVantage has successfully detected cancer at all stages; however, the number of patients at each stage of cancer was too small to derive stage-specific sensitivity data. A similar test demonstrated a sensitivity of 67% and a specificity of 88% in a prospective study of almost 8000 people.10

A patient whose ColoVantage test result is positive may be at increased risk for CRC, and further evaluation should be considered.

Diagnosis
Tissue Pathology
The vast majority of CRC cases are initially diagnosed by endoscopic biopsy or polypectomy performed during follow-up, diagnostic, or screening colonoscopy. Pathology review assesses the state of neoplasia, histologic grade, the margin of the resection, and the presence or absence of lymphovascular invasion. Histologically, adenomas are classified into 3 types with increasing malignant potential: tubular, tubulovillous, and villous. Larger adenoma size and a high degree of dysplasia within the adenoma also make malignant transformation more likely. Follow-up depends on whether histologic features are favorable or unfavorable (Figure 1).

Figure 1. Suggested Workup for Individuals Screened for or Suspected of Colorectal Cancer

Microsatellite Instability (MSI)
Once CRC is diagnosed, it is important to determine if the cancer is associated with Lynch syndrome. The diagnosis of Lynch syndrome begins with consideration of MSI testing. Colorectal tumors should be tested for MSI when any of the Bethesda criteria are met (Table 3). In a study of 1222 patients with CRC, combining Bethesda criteria with MSI testing was more effective in determining which patients should be tested for MMR mutations than the use of either alone.11

Results are reported as MSI-high (MSI-H), MSI-low (MSI-L), or negative for MSI (microsatellite stable, MSS). An MSI-H result is reported if ≥2 of the 5 National Cancer Institute-recommended markers show instability and requires follow-up with MMR gene mutation testing. Although an MSI-H result is the hallmark of Lynch syndrome, it is also found in 15% to 20% of sporadic CRC cases.12 An MSI-L result, reflecting instability in 1 marker, is found in <10% of Lynch syndrome cases and in most MSI-positive sporadic CRCs. Since MSI results do not rule out Lynch syndrome, MMR gene mutation testing should be considered regardless of MSI status in families with a strong suspicion of Lynch syndrome.

MLH1, MSH2, MSH6, and PMS2 Proteins
Immunohistochemical (IHC) testing for MLH1, MSH2, MSH6, and PMS2 proteins complements MSI testing in that it increases the Lynch syndrome detection rate and guides follow-up genetic testing.13,14 Lynch syndrome is unlikely when the MSI is low or stable and IHC results are normal. When the MSI result is high, it should be followed up with gene mutation testing. Selection of the gene to be tested is guided by the protein expression lost as determined by IHC. Click here for more details.

Follow-up Diagnostic Testing
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, founded by the Centers for Disease Control and Prevention, recommends offering diagnostic testing for Lynch syndrome (eg, BRAF, MLH1, MSH2, MSH6, and/or PMS2 mutations) to patients with newly diagnosed CRC.15 Evidence to recommend a specific testing strategy is currently insufficient. A cost-effective approach is to start with MSI and/or IHC testing then proceed to mutation testing. For more information, including mutation testing offered by Quest Diagnostics, click here.

APC Gene
APC gene mutation testing is appropriate for confirming the diagnosis of FAP, attenuated FAP, Gardner syndrome, and Turcot syndrome. It is also appropriate for assessing risk in family members of affected individuals. Up to 90% of APC mutations are point mutations affecting the amino acid coding sequence or APC mRNA splicing. Another 8% to 12% of APC mutations are gene deletions or duplications. Quest Diagnostics offers 2 tests for APC gene analysis: one detects the point mutations, while the other detects the deletions and duplications.

Presence of a point mutation, deletion, or duplication confirms the diagnosis of FAP or a FAP-like syndrome in a symptomatic individual. Absence, on the other hand, does not rule out the diagnosis. Gene sequencing does not identify all mutations affecting APC mRNA splicing. Deletion/duplication analysis cannot detect deletions or duplications that affect regions of the APC gene not examined in the assay (eg, most of the intronic regions).

An at-risk family member who tests negative for the familial mutation is considered to be unaffected. Such an individual can be screened for CRC in the same manner as members of the general population. An at-risk family member who tests positive for the familial mutation, however, is considered to be affected. An annual sigmoidoscopy or colonoscopy is recommended beginning at age 10 to 12 years. Monitoring for extracolonic manifestations is also recommended.

Determining Prognosis
Tumor staging using either the American Joint Committee on Cancer (AJCC) system or the Dukes system has historically been a powerful tool for determining the prognosis of patients with CRC. Staging can be complemented by laboratory tests.

CellSearch® Circulating Tumor Cells
CellSearch is a blood test that measures circulating tumor cells (CTCs). CTCs are rarely present in healthy individuals and patients with nonmalignant diseases but can be detected in patients with metastatic cancer. In patients with metastatic colorectal cancer, prospective clinical studies have found that the number of CTCs predicts progression-free survival (PFS) and OS before treatment and at first follow-up after initiation of new therapy (Table 5).

Table 5. Prediction of Survival for Patients with Metastatic CRC Based on CTC Count16

CTC Count

(CTCs/7.5mL blood)

Median PFS,

Monthsa

Median OS,

Monthsa

Single measurement

Baseline (prior to therapy)

<3

7.9 18.5

≥3

4.5 9.4

Follow-up (3-5 weeks after start of therapy)

<3

6.8 16.4

≥3

1.9 4.4

Baseline and follow-up measurement (13–20 weeks after start of therapy)

At all time points <3

8.1 18.6

Baseline <3; at last draw ≥3

4.3 7.1

At all time points ≥3

2.2 3.9

Baseline ≥3; at last draw <3

7.2 11.7

CTC, circulating tumor cell.

a Median progression-free survival (PFS) and overall survival (OS) are calculated from the time of blood draw.

Chromosomal Microarray, Oncology, ClariSure® Oligo-SNP, FFPE
The chromosomal microarray is a molecular technique that can be used to detect copy number alterations or loss of heterozygosity in malignant tumor tissue. Similar to cytogenetics, higher numbers of alterations are associated with poor survival.

Chromosome Analysis, Solid Tumor
Chromosomal instability as evidenced by loss of heterozygosity, chromosomal rearrangements, or loss of whole chromosomes is associated with prognosis in sporadic colorectal cancer. A high number of chromosomal abnormalities is associated with poor survival.

DNA Cell Cycle Analysis
DNA cell cycle analysis is used to determine ploidy, specifically aneuploidy (an abnormal complement of chromosomes), in CRC tissue. Because of conflicting data on the association of aneuploidy with a poor outcome, the American Society of Clinical Oncology (ASCO) does not recommend routine testing for ploidy.17

p53 Oncoprotein
Overproduction of p53 oncoprotein serves as a surrogate marker of P53 oncogene mutation, which is a common event in tumorigenesis. p53 oncoprotein abnormalities can be identified by detecting increased levels in tumors by immunohistochemical (IHC) testing. The relative risk (RR) of decreased survival was found to be 1.32 for positive IHC results.18

Selecting Therapy
Colorectal Cancer Mutation Panel (KRAS, PIK3CA, BRAF, NRAS)
KRAS, PIK3CA, BRAF, and NRAS all activate signaling pathways downstream from EGFR. Since such activation is independent of EGFR, they can potentially render EGFR immunotherapies (eg, cetuximab and panitumumab) ineffective. For example, in chemotherapy-refractory patients, fewer than 10% of patients who harbor KRAS, BRAF, or NRAS mutations respond to EGFR immunotherapy.19,20 So testing for mutations in these genes may help predict response to cetuximab and panitumumab.

Current guidelines recommend KRAS mutation testing prior to prescribing EGFR antagonist therapy for patients with metastatic CRC; alternative therapy should be prescribed when mutations are detected.21,22 When KRAS is mutation-negative, the National Comprehensive Cancer Network (NCCN) suggests considering BRAF mutation testing.21

PIK3CA mutations may overlap with mutations in BRAF, KRAS, and NRAS,20 but BRAF, KRAS, and NRAS mutations are almost always mutually exclusive (ie, mutations in only 1 of the 3 genes occur within any individual tumor). Thus, analysis of all 4 of these genes could be clinically useful. For more information click here.

Mutation in any of the 4 genes is associated with resistance to cetuximab and panitumumab (Figure 2).

Figure 2. Mutation Testing Results Predict Response to Anti-EGFR Immunotherapy in Patients with Metastatic Colorectal Cancer

Microsatellite Instability
MSI status may be predictive of response to fluoropyrimidine-based (eg, 5-fluorouracil [5-FU]) adjuvant therapy. Among stage II and III colon cancer patients receiving 5-FU, those with MSI-H tumors received less survival benefit than those with MSS tumors.23 Furthermore, patients with MSI-H tumors showed no survival improvement when treated with chemotherapy compared with surgery only.24 Thus, the NCCN recommends that MSI testing be considered for stage II patients who are candidates for single-agent fluoropyrimidine therapy.21 Figure 1 shows how MSI testing can be incorporated into the workup of patients with CRC.

UGT1A1 Polymorphism
Irinotecan (Camptosar®) therapy can result in dose-limiting toxicity manifesting as neutropenia, diarrhea, and asthenia. The risk of toxicity can be assessed by testing for an additional TA repeat in the promoter region of the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1).25,26 This hepatic enzyme metabolizes SN-38, the active form of irinotecan and the cause of drug toxicity.

The presence of an additional TA repeat (ie, positive for TA repeat) is consistent with reduced UGT1A1 enzyme activity and SN-38 metabolism, leading to increased likelihood of irinotecan toxicity. Consequently, the irinotecan product insert suggests a reduced initial dose for patients homozygous for the TA repeat.27 Heterozygous patients have intermediate enzyme activity and may be at increased risk for neutropenia; however, such patients have been shown to tolerate normal initial doses.26 Patients negative for the TA repeat are the least likely to suffer from dose-limiting toxicity. The UGT1A1 TA repeat assay does not detect other mutations in the UGT1A1 gene that may affect UGT1A1 enzyme activity.

Monitoring CRC
Carcinoembryonic Antigen (CEA)
A CEA level, if elevated preoperatively, can be used to detect residual disease following surgery for primary CRC. If tumor removal is complete, the CEA level should return to normal within about 6 weeks following surgery; persistently elevated levels suggest residual or metastatic disease. Approximately 50% of patients who undergo surgery with curative intent develop recurrent or metastatic disease.28 Serial CEA monitoring postsurgery is useful for detecting these conditions. ASCO recommends testing every 3 months for at least 3 years following diagnosis of stage II or III disease, providing the patient is a candidate for further surgery or systemic therapy.17 While stable or falling CEA levels suggest no disease progression, elevated levels, if confirmed by retesting, are associated with disease progression and warrant reevaluation for recurrent and metastatic disease.

For stage IV CRC (distant metastases), CEA is the marker of choice for monitoring chemotherapy: it should be measured before treatment and every 1 to 3 months during treatment.17 While decreases in CEA levels suggest a favorable treatment response, persistently rising values above pretreatment levels suggest disease progression. Rising values should prompt reevaluation and consideration of alternative treatment.17,28 However, transient increases are not always associated with disease progression (eg, within 2 weeks following 5-FU-based treatment and within 4 to 6 weeks after oxaliplatin therapy).17,29 Thus, timing of sample collection for CEA determination should be considered in context with the therapy prescribed.

Although there is no universally accepted definition of what constitutes a clinically significant change in CEA levels, guidelines have been proposed: 1) ≥30% increase over the previous value, confirmed by a second sample collected within 1 month; or 2) >15% increase maintained over ≥3 successive samples.28

Since roughly 25% of patients with CRC do not have elevated levels CEA levels, monitoring treatment with alternative tumor markers such as CA 19-9 may be beneficial.28 However, ASCO does not recommend the routine use of these markers.17

References [return to contents]

  1. American Cancer Society: Cancer facts and figures 2013. Available at: http://www.cancer.org/acs/groups/
    content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed May 02, 2013.

  2. Engstrom PF. Colorectal Cancer. In: Lenhard RE, Osteen RT, Gansler T, ed. Clinical Oncology. Atlanta, GA: American Cancer Society Inc; 2001:361-371.

  3. Genetics of Colorectal Cancer (PDQ®). Available at: http://www.cancer.gov/cancertopics/pdq/genetics/
    colorectal/HealthProfessional/page1. Accessed October 24, 2012.

  4. Rex DK, Johnson DA, Anderson JC, et al; American College of Gastroenterology. American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008. Am J Gastroenterol. 2009;104:739-750.

  5. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: A joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterol. 2008;134:1570-1595.

  6. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-268.

  7. Cole SR, Young GP, Esterman A, et al. A randomized trial of the impact of new faecal haemoglobin test technologies on population participation in screening for colorectal cancer. J Med Screen. 2003;10:117-122.

  8. Levin B, Brooks D, Smith RA, et al. Emerging technologies in screening for colorectal cancer: CT colonoscopy, immunochemical fecal occult blood tests, and stool screening using molecular markers. CA Cancer J Clin. 2003;53:44-55.

  9. Data on file at Quest Diagnostics.

  10. Rösch T, Church T, Osborn N, et al. Prospective clinical validation of an assay for methylated SEPT9 DNA for colorectal cancer screening in plasma of average risk men and women over the age of 50 [abstract]. Gut. 2010;59(suppl III):A307.

  11. Pinol V, Castells A, Andreu M, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005;293:1986-1994.

  12. Cruz-Correa M, Giardiello FM. Diagnosis and management of hereditary colon cancer. Hematol Oncol Clin N Am. 2003;17:539-551.

  13. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology. Colorectal cancer screening. Version 2.2012. Available at: http://www.nccn.org/professionals/physician_gls/pdf/colorectal_
    screening.pdf. Accessed May 6, 2013.

  14. Pino MS, Chung DC. Application of molecular diagnostics for the detection of Lynch syndrome. Expert Rev Mol Diagn. 2010;10:651-665.

  15. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11:35-41.

  16. CellSearch® Circulating Tumor Cell Kit (Epithelial) [package insert]. Raritan, NJ: Veridex LLC. LBL 50058, Rev. 6, 2009-05. Available at: http://www.veridex.com/pdf/7800047_04.pdf. Accessed November 5, 2012.

  17. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24:5313-5327.

  18. Munro AJ, Lain S, Lane DP. P53 abnormalities and outcomes in colorectal cancer: A systematic review. Br J Cancer. 2005;92:434-444.

  19. Heinemann V, Stintzing S, Kirchner T, et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2009;35:262-271.

  20. DeRoock W, Claes B, Bernasconi D, et al. 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. 2010;11:753-762.

  21. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology. Colon cancer. Version 2.2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed May 6, 2013.

  22. Allegra CJ, Jessup JM, Somerfield MR, et al. 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. 2009;27:2091-2096.

  23. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-1896.

  24. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219-3226.

  25. Massacesi C, Terrazzino S, Marcucci F, et al. Uridine diphosphate glucuronosyl transferase 1A1 promotor polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer. 2006;106:1007-1016.

  26. Rouits E, Boisdron-Celle M, Dumont A, et al. Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res. 2004;10:5151-5159.

  27. Camptosar [package insert]. New York, NY: Pfizer Inc; 2006.

  28. Duffy MJ, vanDalen A, Haglund C, et al. Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines. Eur J Cancer. 2003;39:718-727.

  29. Sorbye H, Dahl O. Transient CEA increase at start of oxaliplatin combination therapy for metastatic colorectal cancer. Acta Oncologica. 2004;43:495-498.
     

Content reviewed 05/2013

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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.