Approximately 5% to 6% of cases of colorectal cancer are associated with germline mutations conferring an inherited predisposition for disease. As reported by Stoffel and colleagues in the Journal of Clinical Oncology,¹ ASCO has endorsed, with qualifying statements, the European Society for Medical Oncology (ESMO) 2013 guideline on familial-risk colorectal cancer.² The ASCO endorsement panel was co-chaired by Elena M. Stoffel, MD, of University of Michigan, Ann Arbor, and Paul J. Limburg, MD, of the Mayo Clinic, Rochester, ­Minnesota.

Major Guideline Principles

In brief, the guideline states that the possibility of hereditary cancer syndrome should be assessed for every patient at the time of colorectal cancer diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management of patients with colorectal cancer and their family members.

Screening for hereditary cancer syndromes should include review of personal and family histories and testing of tumors for DNA mismatch-repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria.

The summary of recommendations here uses or paraphrases the language of the original ESMO recommendations, with ASCOqualifying statements appearing in italics.

Testing and Management

• Tumor testing for DNA mismatch-repair deficiency with immunohistochemistry for mismatch-repair proteins or microsatellite instability should be assessed in all colorectal cancer patients. As an alternative strategy, tumor testing should be carried out in colorectal cancer patients aged < 70 years and in those aged > 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 of MLH1 promoter methylation should be performed first to rule out a sporadic case. If tumor is mismatch-repair 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.
• Follow-up in mutation carriers includes colonoscopy every 1 to 2 years and gynecologic examination (with transvaginal ultrasound and aspiration biopsy) yearly. Prophylactic gynecologic surgery may be an option in female carriers from age 35 and after childbearing is completed.
• Individuals with familial colorectal cancer X syndrome should have colonoscopy at 3- to 5-year intervals, starting 5 to 10 years earlier than the youngest case in the family.
• Patients with multiple colorectal adenomas (> 10) should be considered for germline genetic testing of APC and/or MUTYH.
• Full germline genetic testing of APC should include DNA sequencing and large rearrangement analysis.
• Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the white population followed by analysis of the entire gene in heterozygotes. Founder mutations among ethnic groups should be taken into account. For nonwhite individuals, full sequencing of MUTYH should be considered.
• In families with classic familial adenomatous polyposis, sigmoidoscopy (or colonoscopy) should be carried out every 1 to 2 years starting at the age of 10 to 11 years and continued lifelong in mutation carriers. Surgery is indicated if there are large numbers of adenomas, including adenomas with a high degree of dysplasia.
• In families with attenuated familial adenomatous polyposis, colonoscopy should be carried out every 2 years starting at the age of 18 to 20 years and continued lifelong in mutation carriers. Surgery is indicated if there are large numbers of adenomas, including adenomas with a high degree of dysplasia. Some patients with attenuated familial adenomatous polyposis can be conservatively managed with a colonoscopy every 1 to 2 years and polypectomy.
• Type of colorectal surgery in familial adenomatous polyposis (total colectomy plus ileorectal anastomosis vs proctocolectomy plus ileal pouch anal anastomosis) depends on age of the patient, severity of rectal polyposis, wish to have children, risk of developing desmoids, and possibly the site of the mutation in the APC gene.
• After colorectal surgery, surveillance of the rectum or pouch should be carried out every 6 to 12 months if rectal tissue remains and every 6 months to 5 years if ileoanal pouch is present, depending on polyp burden. Surveillance of the gastroduodenum should be performed every 6 months to 5 years depending on polyp burden.
• In both classic and attenuated familial adenomatous polyposis, screening for extracolonic manifestations (gastroduodenal polyposis, thyroid cancer, desmoid tumors) should be considered when colorectal polyposis is diagnosed or at the age of 25 to 30 years, whichever comes first.
• The suggested surveillance protocol for MUTYH-associated polyposis patients is similar to that for patients with attenuated familial adenomatous polyposis.

Surveillance Recommendations

Lynch Syndrome

• Colon and rectum: Colonoscopy every 1 to 2 years, starting at age 20 to 25, or 5 years before the youngest case in the family. No upper limit established.
• Endometrium and ovaries: Gynecologic examination, pelvic ultrasound (not CA-125), and aspiration biopsy every year, from age 30 to 35 years. Consider prophylactic hysterectomy and salpingoophorectomy when childbearing is completed.
• Gastric cancer: Search for Helicobacter pylori, and subsequent eradication is recommended in mutation carriers. In case of a high incidence of gastric cancer in some populations, some experts recommend upper gastrointestinal endoscopy every 1 to 3 years.
• Other Lynch-associated cancers: Surveillance is not recommended due to low sensitivity and specificity. (Although there are insufficient data supporting surveillance for other target organs, it may be considered in the context of family history.)

Classic Familial Adenomatous Polyposis

• Colon and rectum: Sigmoidoscopy (or colonoscopy) every 1 to 2 years, starting at age 10 to 11 years and continued lifelong in mutation carriers. Once adenomas are detected, annual colonoscopy should be carried out until colectomy is planned. Surgery is indicated if there are large numbers of adenomas, including adenomas with a high degree of dysplasia.
• Gastroduodenal adenomas: Gastroduodenal endoscopy using both front- and side-view scopes 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 considered starting at age 25 to 30 years.
• Desmoid tumors: A baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan should be considered if risk factors (positive family history for desmoids and site of the mutation in APC).

Attenuated Familial Adenomatous Polyposis

• 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 using both front- and side-view scopes 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 considered starting at age 25 to 30 years.
• Desmoid tumors: A baseline CT scan or MRI should be considered if risk factors are present (positive family history for desmoids and site of the mutation in APC). ■

Disclosure: For full disclosures of the ASCO panel members, visit jco.ascopubs.org.

References

1. Stoffel EM, Mangu PB, Grube SB, et al: Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk–colorectal cancer: European Society for Medical Oncology clinical practice guidelines. J Clin Oncol 33:209-217, 2015.

2. Balmaña J, Balaguer F, Cervantes A, et al: Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol 24(suppl 6):vi73-vi80, 2013.