Colorectal Cancer Guidelines 

Updated: Mar 27, 2017
  • Author: Elwyn C Cabebe, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Colorectal Cancer Screening

Guidelines on colorectal screening have been issued by the following organizations:

  • American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology
  • U.S. Preventive Services Task Force (USPSTF)
  • American College of Physicians (ACP)
  • American College of Gastroenterology (ACG)
  • National Comprehensive Cancer Network (NCCN)

While all the guidelines recommend routine screening for colorectal cancer and adenomatous polyps in asymptomatic adults starting at age 50, they differ with regard to frequency of screening and age at which to discontinue screening, as well as the preferred screening method. For high-risk patients, the recommendations differ regarding the age at which to begin screening, as well as the frequency and method of screening.

American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology

A joint guideline developed by the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommends that screening for colorectal cancer and adenomatous polyps start at age 50 years in asymptomatic men and women. [1]

In addition, individuals with any of the following colorectal cancer risk factors should undergo colonoscopy at an earlier age and more frequently than average risk individuals:

  • Family history of colorectal cancer or polyps
  • Family history of a hereditary colorectal cancer syndrome such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC)
  • Personal history of colorectal cancer
  • Personal history of chronic inflammatory bowel disease (ulcerative colitis or Crohn disease)

Screening options for average-risk adults consist of tests that detect adenomatous polyps and cancer, and tests that primarily detect cancer. Any one of these tests can be used for screening.

Tests that detect adenomatous polyps and cancer, and their recommended frequency, include the following:

  • Flexible sigmoidoscopy every 5 years
  • Colonoscopy every 10 years
  • Double-contrast barium enema every 5 years
  • Computed tomographic (CT) colonography every 5 years

Tests that primarily detect cancer, and their recommended frequency, include the following:

  • Annual guaiac-based fecal occult blood test (FOBT) with high test sensitivity for cancer
  • Annual fecal immunochemical test (FIT) with high test sensitivity for cancer
  • Stool DNA test with high sensitivity for cancer, interval uncertain

U.S. Preventive Services Task Force (USPSTF)

The USPSTF recommends that screening for colorectal cancer start at age 50 years and continue until age 75 years (A recommendation). For adults aged 76 to 85 years, the decision to screen should be individualized, taking into account the patient’s overall health and prior screening history (C recommendation). [2]

The USPSTF advises that screening is more likely to benefit older patients who have never been screened than those who have undergone screening, and is more likely to benefit patients who are healthy enough to undergo treatment for colorectal cancer treatment and who do not have other medical conditions limiting their life expectancy. [2]

The USPSTF does not recommend colorectal cancer screening for adults older than 85 years. [2]

The USPSTF notes that colorectal screening is substantially underused. As part of a strategy to increase screening rates, the guidelines provide a range of screening options rather than a ranking of tests.

Stool-based screening tests and intervals are as follows:

  • Guaiac-based fecal occult blood test (FOBT), every year
  • Fecal immunochemical test (FIT), every year
  • FIT-DNA, every 1 or 3 years

Direct visualization screening tests and intervals are as follows:

  • Colonoscopy, every 10 years
  • Computed tomographic (CT) colonography, every 5 years
  • Flexible sigmoidoscopy, every 5 years
  • Flexible sigmoidoscopy with FIT; sigmoidoscopy every 10 years, with FIT every year

American College of Physicians (ACP)

In 2015, the American College of Physicians recommended that average-risk adults aged 50 to 75 years should be screened for colorectal cancer by one of the following strategies [3] :

  • Annual high-sensitivity FOBT or FIT
  • Flexible sigmoidoscopy every 5 years
  • High-sensitivity FOBT or FIT every 3 years plus flexible sigmoidoscopy every 5 years
  • Colonoscopy every 10 years

Interval screening with fecal testing or flexible sigmoidoscopy in adults having 10-year screening colonoscopy is not recommended. Average-risk adults younger than 50 years, older than 75 years, or with an estimated life expectancy of less than 10 years should not be screened. 

American College of Gastroenterology (ACG)

The guidelines of the American College of Gastroenterology make a distinction between screening tests for cancer prevention and those for cancer detection. [4] The specific guidelines for colorectal cancer screening are as follows:

  • Tests that prevent cancer are preferred over those that only detect cancer
  • The preferred colorectal cancer prevention test is colonoscopy every 10 years, beginning at age 50 years, but at age 45 years in African Americans
  • For patients who decline colonoscopy or another cancer prevention test, the preferred cancer detection test is FIT, conducted annually

Alternative cancer detection tests recommended in the ACG guidelines are as follows:

  • Flexible sigmoidoscopy every 5-10 years
  • CT colonography every 5 years, which replaces double contrast barium enema as the radiographic screening alternative for patients who decline colonoscopy

Alternative cancer detection tests in the ACG guidelines are as follows:

  • Annual Hemoccult Sensa
  • Fecal DNA testing every 3 years

For screening purposes, patients with one first-degree relative diagnosed with colorectal cancer or advanced adenoma at age 60 years or older are considered at average risk. For patients with a single first-degree relative diagnosed with colorectal cancer or advanced adenoma before age 60 years, or those with two first-degree relatives with colorectal cancer or advanced adenomas, the guideline recommends colonoscopy every 5 years, beginning at age 40 years or at 10 years younger than the age at diagnosis of the youngest affected relative.

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (NCCN) has released separate guidelines for average-risk and high-risk individuals. [5, 6] For average individuals, the recommendations are nearly identical to those of the joint American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology.

The NCCN guidelines provide screening recommendations for patients at increased risk due to any of the following [5] :

  • Personal history of adenoma or sessile serrated polyp
  • Personal history of colorectal cancer
  • Inflammatory bowel disease
  • Positive family history

The guidelines also specify recommendations for patients with the following high-risk syndromes [6] :

  • Lynch syndrome
  • Familial adenomatous polyposis (FAP)
  • Attenuated familial adenomatous polyposis (AFAP)
  • MUTHYH-associated polyposis
  • Peutz-Jeghers syndrome (PJS)
  • Juvenile polyposis syndrome (JPS)
  • Serrated polyposis syndrome (SPS)
  • No syndrome identified, but familial risk present

Individuals meeting one or more of the following criteria should receive further evaluation for high-risk syndromes:

  • Individuals meeting the revised Bethesda Guidelines (Lynch Syndrome)
  • Family members meeting Amsterdam criteria (Lynch Syndrome)
  • Individuals with more than 10 adenomas detected ( MUTYH)
  • Individuals with multiple GI hamartomatous polyps (PJS and JPS)
  • Family members with a known high-risk syndrome associated with colorectal cancer, with or without a known mutation
  • Individuals with a desmoid tumor

Screening for Familial Risk

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Guidelines for Lynch syndrome screening have been developed by the National Cancer Institute (Bethesda guidelines) and the National Comprehensive Cancer Network (NCCN). [7]

The American Gastroenterological Association recommends testing all patients with colorectal cancer for Lynch syndrome; the tumor should be tested for MSI or with immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins. [8]

The European Society for Medical Oncology (ESMO) guidelines for familial risk-colorectal cancer [9] , which have been endorsed by the American Society of Clinical Oncology (ASCO) [10] includes the following recommendations:

  • Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all patients with colorectal cancer. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines
  • If loss of MLH1/PMS2 protein expression is observed, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be conducted to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.
  • If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1).
  • Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis.

The American College of Gastoenterology recommendations are in general agreement with ESMO. [11]

Revised Bethesda guidelines for Lynch syndrome and microsatellite instability

Because cancers with MSI account for approximately 15% of all colorectal cancers, in 1996 the National Cancer Institute developed the Bethesda guidelines for the identification of individuals with HNPCC who should be tested for MSI. These guidelines were most recently revised in 2002. [12]

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Postpolypectomy Surveillance

The American College of Gastroenterology has published guidelines for surveillance of patients who have had adenomas detected and removed at colonoscopy. [13]

These patients should have more frequent followup, as they are at increased risk for developing metachronous adenomas or colon cancer.

Colonoscopy findings and recommended scheduling of followup colonoscopy are as follows:

  • No polyps – 10 years
  • Small (<10 mm) hyperplastic polyps in rectum or sigmoid – 10 years
  • 1–2 small (<10 mm) tubular adenomas – 5- 10 years
  • 3–10 tubular adenomas – 3 years
  • 10 adenomas – <3 years
  • One or more tubular adenomas ≥10 mm – 3 years
  • One or more villous adenomas – 3 years
  • Adenoma with high-grade dysplasia – 3 years

For serrated lesions, recommended surveillance intervals are as follows:

  • Sessile serrated polyp(s) <10 mm with no dysplasia – 5 years
  • Sessile serrated polyp(s) ≥10 mm with no dysplasia – 3 years
  • Sessile serrated polyp with dysplasia – 1 year
  • Traditional serrated adenoma – 1 year
  • Serrated polyposis syndrome – 1 year
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Familial Adenomatous Polyposis

The European Society of Medical Oncology offers the following recommendations for surveillance of patients with familial adenomatous polyposis (FAP) [9] :

Classic FAP

  • Colon and rectum: Sigmoidoscopy (or colonoscopy) every 1 to 2years, starting at age 10 to 11 years and continued lifelong in mutation carriers. Once adenomas are detected, annual colonoscopy until colectomy. Surgery is indicated if there are large numbers of adenomas, including adenomas showing a high degree of dysplasia.
  • Gastroduodenal adenomas: Gastroduodenal endoscopy starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage.
  • Thyroid cancer:  Consider annual cervical ultrasonography starting at age 25 to 30 years.
  • Desmoid tumors: Consider baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan in presence of risk factors (positive family history for desmoids and site of the mutation in APC).

Attenuated FAP

  • Colon and rectum: Colonoscopy every 1 to 2 years, starting at age 18 to 20 years and continued lifelong in mutation carriers. Once adenomas are detected, colonoscopy should be carried out annually.
  • Gastroduodenal adenomas: Gastroduodenal endoscopy starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage.
  • Thyroid cancer: Annual cervical ultrasonography may be consideredstarting at age 25 to 30 years.
  • Desmoid tumors: A baseline CT scan or MRI should be considered if risk factors (positive family history for desmoids and site of the mutation in APC).

The American Society of Colon and Rectal Surgeons recommends that patients with familial adenomatous polyposis (FAP) or with personal or family risk factors for FAP be referred to center registries and genetic counselors with experience in the multidisciplinary management of these individuals. [14]

Additional recommendations include the following:

  • Prophylactic colectomy or proctocolectomy should be routine; the frequency and type of surgery should depend on the severity of the polyposis phenotype
  • Use of chemoprevention as primary therapy is not recommended
  • Small tubular adenomas with mild dysplasia can be kept under surveillance, but adenomas with severe dysplasia must be removed
  • Duodenectomy or pancreaticoduodenectomy is recommended for persistent or recurrent severe dysplasia in the papilla or duodenal adenomas
  • Clinically inert tumors should be treated with sulindac or not treated at all
  • Slowly growing or mildly symptomatic tumors may be treated with less toxic regimens such as sulindac and tamoxifen or with vinblastine and methotrexate
  • Rapidly growing tumors need aggressive therapy with either very-high-dose tamoxifen or antisarcoma-type chemotherapy
  • Radiation is an option if collateral damage is not a major concern

 

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Surgical Treatment for Colon Cancer

The American Society of Colon and Rectal Surgeons practice parameters for the management of colon cancer recommend colectomy as the primary treatment for localized resectable colon cancer. [15]

Additional recommendations are as follows:

  • The extent of resection of the colon should correspond to the lymphovascular drainage of the site of the colon cancer; the lymphadenectomy should be complete and en bloc with the bowel segment
  • Clinically positive lymph nodes located outside the standard field of resection that are suspected to contain metastatic disease should be biopsied or removed at the time of primary resection
  • Resection of involved adjacent organs should be en bloc

National Comprehensive Cancer Network (NCCN) guidelines also recommend colectomy, with en bloc removal of regional lymph nodes, for treatment of resectable, nonobstructing colon cancer. [7] In addition, for clinical T4b disease, neoadjuvant chemotherapy may be considered. The NCCN states that laparoscopic-assisted colectomy may be considered, based upon the following criteria:

  • The surgeon has experience performing laparoscopically assisted colorectal operations
  • No locally advanced disease, acute bowel obstruction, or perforation from cancer is present
  • Thorough abdominal exploration is required
  •  Preoperative marking of small lesions should be considered 

NCCN recommendations for lymphadenectomy are as follows [7] :

  • Lymph nodes at the origin of feeding vessel should be identified for pathologic exam
  • Clinically positive lymph nodes outside the field of resection that are considered suspicious should be biopsied or removed, if possible
  • Positive nodes left behind indicate an incomplete (R2) resection
  • A minimum of 12 lymph nodes need to be examined to establish N stage
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Surgical Treatment for Rectal Cancer

The American Society of Colon and Rectal Surgeons (ASCRS) defines rectal cancer as cancer located within 15 cm of the anal verge by rigid proctoscopy. ASCRS 2013 revised management guidelines and practice parameters recommend that patients with low-risk, early-stage rectal cancer be treated with primary surgical therapy. Treatment of locally advanced or high-risk disease should include neoadjuvant radiation or chemoradiation followed by surgery. [16]

Additional recommendations include the following [16] :

  • Local excision for T1 tumors absent high risk factors
  • Total mesorectal excision (TME) for curative resection of tumors of the middle and lower thirds of the rectum
  • In the absence of clinical involvement, extended lateral lymph node dissection (LLND) is not necessary in addition to TME
  • For tumors of the upper third of the rectum, a tumor-specific mesorectal excision should be used.
  • For T4 rectal cancers, resection of involved adjacent organs should be performed with an en bloc technique.
  • Oophorectomy is advised for grossly abnormal ovaries or contiguous extension of a rectal cancer, but routine prophylactic oophorectomy is not necessary
  • Laparoscopic TME has comparable outcomes with open TME

 

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Adjuvant Therapy for Colorectal Cancer

National Comprehensive Cancer Network (NCCN) guidelines recommend the use of as many chemotherapy drugs as possible to maximize the effect of adjuvant therapies for colon and rectal cancer. [7, 17]

The American Society of Clinical Oncology does not recommend the routine use of adjuvant chemotherapy for patients with stage II colon cancer, and instead recommends encouraging these patients to participate in clinical trials. [18]

According to the NCCN, stage I (T1-2, N0, M0) rectal cancer patients do not require adjuvant therapy due to their high cure rate with surgical resection. High-risk patients, including those with poorly differentiated tumor histology and those with lymphovascular invasion, should be considered for adjuvant chemotherapy and radiotherapy.

The NCCN guidelines recommend combination therapy with infusional fluorouracil, folinic acid, and oxaliplatin (FOLFOX) as reasonable for patients with high-risk or intermediate-risk stage II disease; however, FOLFOX is not indicated for good- or average-risk stage II rectal cancer. Adjuvant chemotherapy is encouraged for eligible patients with stage III disease.

For more information on chemotherapy regimens, see Colon Cancer Treatment Protocols.For the majority of patients with stage II or stage III rectal cancer, the NCCN recommends the use of ionizing radiation to the pelvis along with adjuvant chemotherapy. Either of the two following sequences of therapy may be used:

  • Chemoradiation therapy preoperatively and chemotherapy postoperatively
  • Chemotherapy followed by chemoradiation therapy, followed by resection

The NCCN advises that the total duration of perioperative therapy, including chemoradiation therapy and chemotherapy, should not exceed 6 months.

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Follow-up Care in Stage II and III Colorectal Cancer

Guidelines on follow-up care for survivors of stage II and stage III colorectal cancer were issued by the following organizations:

  • Cancer Care Ontario endorsed by American Society of Clinical Oncology (ASCO)
  • European Society of Medical Oncology (ESMO)
  • National Comprehensive Cancer Network (NCCN)
  • American Society of Colon and Rectal Surgeons (ASCRS)

All four guidelines agree that patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection, and that surveillance should include regular reviews of medical history, physical examination, and carcinoembryonic antigen assays, as well as colonoscopy and abdominal and chest computed tomography (CT [19, 20, 7, 21] The frequency of the surveillance testing differs as shown in the table below.

Table.1 (Open Table in a new window)

Parameter Organization
ESMO (2013) [20] ASCO (2013) [22] NCCN  (2016) [7] ASCRS (2015) [21]
History and physical exam Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y Every 3-6 mo for 3 y, then every 6 mo to 5 y Every 3-6 mo for 2 y, then every 6 mo to 5 y Every 3-6 mo for 2 y, then every 6 mo to 5 y
CEA Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y Every 3 mo for 3 y* Every 3-6 mo for 2 y, then every 6 mo to 5 y Every 3-6 mo for 2 y, then every 6 mo to 5 y
Chest CT* Every 6-12 mo for first 3 y Every 1 y for 3 y Every 1 y for 5 y Every 1 y for 5 y
Colonoscopy** At y 1 after surgery, and every 3-5 y thereafter At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy At 1 y, 3 y, and 5 y if negative At y 1 after surgery, and every 3-5 y dictated by the findings on the first postoperative examination.
Abdominal CT* Every 6-12 mo for first 3 y Every 1 y for 3 y Every 1 y for 5 y; scans to include pelvis Every 1 y for 5 y
ESMO = European Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; American Society of Colon and Rectal Surgeons = ASCRS CEA = carcinoembryonic antigen; CT = computed tomography * For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors). **Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp >1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y.

In 2016, the US Multi-Society Task Force on Colorectal Cancer issued guidelines on colonoscopy after colorectal cancer resection, which included the following recommendations [22] :

  • Patients with colorectal cancer (CRC) should undergo high-quality perioperative clearing with colonoscopy. The procedure should be performed preoperatively, or within a 3- to 6-mo interval after surgery in the case of obstructive CRC. The goals of perioperative clearing colonoscopy are detection of synchronous cancer and detection and complete resection of precancerous polyps.
  • Patients who have undergone curative resection of either colon or rectal cancer should receive their first surveillance colonoscopy 1 yr after surgery (or 1 yr after the clearing perioperative colonoscopy).
  • Patients with localized rectal cancer who have undergone surgery without total mesorectal excision, those who have undergone transanal local excision (ie, transanal excision or transanal endoscopic microsurgery) or endoscopic submucosal dissection, and those with locally advanced rectal cancer who did not receive neoadjuvant chemoradiation and then surgery using total mesorectal excision techniques, are at increased risk for local recurrence. In these situations, it is suggested that patients undergo local surveillance with flexible sigmoidoscopy or endoscopic ultrasound (EUS) every 3−6 mo for the first 2−3 yr after surgery. These surveillance measures are in addition to recommended colonoscopic surveillance for metachronous neoplasia.
  • In patients with obstructive CRC precluding complete colonoscopy, CT colonography (CTC) is recommended as the best alternative to exclude synchronous neoplasms. Double-contrast barium enema is an acceptable alternative if CTC is not available.
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Molecular Biomarker Testing

Guidelines on molecular biomarker testing for the evaluation of colorectal cancer (CRC) from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology include the following recommendations [23] :

  • Patients with CRC who are being considered for anti–epidermal growth factor receptor (EGFR) therapy must receive RAS mutational testing, which should include KRAS and NRAS codons 12 and 13 of exon 2, 59 and 61 of exon 3, and 117 and 146 of exon 4 (“expanded” or “extended” RAS).
  • BRAF p.V600 ( BRAF c.1799 [p.V600]) position mutational analysis should be performed in CRC tissue in selected patients for prognostic stratification.
  • BRAF p.V600 mutational analysis should be performed in deficient mismatch repair (dMMR) tumors with loss of MLH1 to evaluate for Lynch syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome.
  • Clinicians should order mismatch repair status testing in patients with CRC to identify patients at high risk for Lynch syndrome and/or for prognostic stratification.
  • Tissues from metastatic or recurrent CRC tumors are the preferred specimens for treatment-predictive biomarker testing and should be used if such specimens are available and adequate. In their absence, primary tumor tissue is an acceptable alternative and should be used.
  • Formalin-fixed, paraffin-embedded (FFPE) tissue is an acceptable specimen for molecular biomarker mutational testing in colorectal carcinoma. Use of other specimens (eg, cytology specimens) will require additional adequate validation, as would any changes in tissue-processing protocols.
  • Laboratories must validate the performance of immunohistochemistry (IHC) testing for CRC molecular biomarkers (currently IHC testing for MLH1, MSH2, MSH6, and PMS2) in accordance with best laboratory practices.
  • Laboratories should use CRC molecular biomarker testing methods that are able to detect mutations in specimens with at least 5% mutant allele frequency, taking into account the analytical sensitivity of the assay (limit of detection [LOD]) and tumor enrichment (eg, microdissection).

The 2016 European Society of Medical Oncology (ESMO) guidelines for the management of patients with metastatic CRC (mCRC) include the following recommendations on biomarker testing [24] :

  • RAS mutational testing should be carried out on all patients at the time of diagnosis of mCRC , as the presence of RAS mutations is a negative predictive biomarker for response to EGFR antibody therapy for mCRC.
  • RAS testing is mandatory before treatment with the EGFR-targeted monoclonal antibodies cetuximab and panitumumab [I, A].
  • Primary or metastatic colorectal tumor tissue can be used for RAS testing.
  • RAS analysis should include at least KRAS exons 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) and NRAS exons 2, 3 and 4 (codons 12, 13, 59, 61 and 117).
  • Tumor BRAF mutation status should be assessed along with RAS mutational status for prognostic assessment (and/or potential selection for clinical trials).
  • Microsatellite instability (MSI) testing in the setting of mCRC can provide helpful information for genetic counselling and has strong predictive value for the use of immune check-point inhibitors (eg, pembrolizumab)
  • Dihydropyrimidine dehydrogenase (DPD) testing before fluorouracil (5-FU) administration remains an option but is not routinely recommended; however, it should be done before reintroducing 5-FU in patients who have experienced severe 5-FU toxicity.
  • UGT1A1 phenotyping remains an option for predicting irinotecan toxicity and should be carried out when UGT1A1 deficiency is suspected (on the basis of low conjugated bilirubin levels) and when an irinotecan dose of >180 mg/m 2 per administration is planned.
  • Thymidylate synthase (TS) activity and  TSER genotyping for predicting response to 5-FU are not recommended for use in clinical practice
  • Testing of excision repair cross-complementation group 1 (ERCC1) protein expression for treatment decisions involving the use of oxaliplatin is not recommended outside of clinical trials.

The ESMO guidelines do not recommend the following emerging biomarkers for routine patient management outside of a clinical trial setting:

  • Mutations in PIK3CA, exon 20
  • PTEN loss by IHC
  • Levels of the EGFR ligands amphiregulin, epiregulin and TGF-α
  • Levels of EGFR protein expression
  • EGFR amplification and copy number and EGFR ectodomain mutations
  • HER2 amplification or HER2 activating mutations
  • HER3 and MET receptor overexpression
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