ASCO Endorses Guidelines for Hereditary Colorectal Cancers

Roxanne Nelson

December 04, 2014

The American Society of Clinical Oncology (ASCO) has endorsed guidelines previously issued by the European Society for Medical Oncology (ESMO) for individuals at risk for hereditary colorectal cancer syndromes — with a few caveats.

The ESMO recommendations, published last year (Ann Oncol. 2013;24[Suppl 6]:vi73-vi80), cover prevention, screening, genetics, treatment, and management of such individuals.

The ASCO endorsement was published online December 1 in the Journal of Clinical Oncology.

ASCO is in agreement with nearly everything in the ESMO guidelines, except  a few minor points, said Elena M. Stoffel, MD, MPH, one of the cochairs of the ASCO Endorsement Panel, which added a few qualifying statements.

Different sets of guidelines have been issued for this group of hereditary cancers, said Dr Stoffel, who is also director of the Cancer Genetics Clinic at the University of Michigan Health System in Ann Arbor. "But it has been several years since we've had any updates, and with the increased amount of genetic testing, it is very important that providers stay up to date," she told Medscape Medical News. "Some of the recommendations have changed since earlier guidelines were issued."

About 5% to 6% of colorectal cancer cases are associated with germline mutations that confer an inherited predisposition for cancer. These include Lynch syndrome, APC-associated familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis, and familial colorectal cancer type X.

Of this group, Lynch syndrome is the most common hereditary syndrome associated with colorectal cancer, and accounts for about 2% to 3% of cases. In addition to colorectal cancer, Lynch syndrome confers a higher risk for other malignancies, including endometrial, stomach, breast, ovarian, small bowel, pancreatic, prostate, urinary tract, liver, kidney, and bile duct cancers.

Main Recommendations With ASCO Qualifications

The ASCO panel agrees with the recommendation that all colorectal cancer patients be assessed for a hereditary cancer syndrome at the time of their cancer diagnosis because it can influence clinical management. Tumors should be tested for DNA mismatch repair deficiency (MMR) with immunohistochemistry for MMR proteins and/or microsatellite instability (MSI).

An alternate strategy calls for tumor testing in people younger than 70 years or in those older than 70 who fulfill any of the revised Bethesda guidelines.

"Our panel favored universal screening, whereas ESMO favored the alternate strategy," said Dr Stoffel. "The Europeans tend to use the age of 70 as the cutoff."

One reason for putting an age limit on screening is that MSI testing is less accurate in older adults. Microsatellites are repeated sequences of DNA, and instability arises when there is a loss of DNA mismatch activity. It is found in the majority of these hereditary cancers, but Dr Stoffel pointed out that MSI also increases with age.

"The specificity for MSI goes down as the patient gets older," she said. "Another issue is the cost involved in testing everyone with colorectal cancer. The Europeans are also more focused on that, whereas here in the United States, we focus on not wanting to miss a diagnosis."

Another difference relates to screening in families with classic FAP. The ESMO guidelines specify that carriers of APC mutations (or those at risk) should undergo sigmoidoscopy every 2 years, beginning at 12 to 14 years of age. In contrast, the ASCO Endorsement Panel recommends initiating colorectal screening with sigmoidoscopy or colonoscopy at 10 or 11 years, and repeating the procedure every 1 to 2 years.

"We tend to use colonoscopy for children with FAP here in the United States, rather than sigmoidoscopy, which is in the ESMO guidelines," Dr Stoffel explained. "The reason for that is to remove as many adenomas as possible before they need to undergo a colectomy."

Also for FAP, ESMO guidelines recommend that after colorectal surgery, surveillance be performed at 1- to 5-year intervals, depending on the polyp burden. The ASCO panel felt that 5-year surveillance intervals might be too infrequent, and that intervals should be determined on a case-by-case basis. Their qualifying statement recommends surveillance every 6 to 12 months if rectal tissue remains, and every 6 months to 5 years if there is an ileoanal pouch.

Qualifications have been made to other screening recommendations.

For instance, full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis.

And for nonwhite individuals, full sequencing of MUTYH should be considered because founder mutations can differ in other ethnic groups.

When loss of MLH1/PMS2 protein expression is observed, analysis of BRAF V600E mutation or of methylation of the MLH1 promoter is needed to rule out sporadic cases. When a tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.

In addition, 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.

ASCO Surveillance Recommendations

Women with Lynch syndrome have a substantial increased lifetime risk for endometrial and ovarian cancer, and Dr Stoffel noted that screening for these cancers is now in the ESMO guidelines. "They favor screening, with consideration for prophylactic surgery," she said. "And we agree that prophylactic removal of the uterus and ovaries might be an option for women after they complete childbearing."

But the ESMO guidelines also recommend testing for cancer antigen 125 as part of the screening program, and the ASCO panel disagrees with that. They say that there are no data to support its annual use in screening.

For other Lynch-associated cancers, the ESMO guidelines say that surveillance is not recommended because of low sensitivity and specificity. But the ASCO panel has added that even though there are insufficient data supporting surveillance for other target organs, it can be considered in the context of family history.

When screening for desmoid tumors in classic FAP and AFAP, ASCO recommends that a baseline CT or MRI scan be considered if there are risk factors (positive family history for desmoids and site of the mutation in APC).

Several of the coauthors report relationships with industry, as detailed in the publication.

J Clin Oncol. Published online December 1, 2014. Abstract


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