Genetic test for Coumadin

M Levin, MD — Sun, 16 Sep 2012 20:32:25 +0000

Warfarin (Coumadin®) dose is sometimes difficult to adjust. Now there is a genetic tests that can identify people who have an increased response to conventional doses of Coumadin, which can cause bleeding. The labeling for a popular formulation of warfarin was revised in August 2007 and February 2010 to include information about how the three most widely studied pharmacogenetic mutations (CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A) affect dose requirements (NDA 9-218/S-105). The Warfarin-Sensitivity test idendifies that most common mutations that affect warfarin metabolism. CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing, VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing. Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing.

Approval was based on a study involved 896 participants with an average age of 65 who were members of prescription benefit plans managed by Medco. Hospitalization rates for this group were matched against a historical control group of 2,688 individuals. Researchers collected DNA from either blood or buccal cells and determined patients’ genotypes for the CYP2C9 and VKORC genetic variants. Mutations in the CYP2C9 gene have been associated with decreased warfarin metabolism, while mutations in the VKORC1 gene are associated with warfarin sensitivity. Based on each individual’s genotype, clinicians used a dosing algorithm to determine that person’s initial dose. The study followed patients for 6 months after the start of their treatment. Compared with the control group, the genotyped patients had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism during the follow-up period. The study results were first reported at theAmericanCollegeof Cardiology’s annual meeting in March of 2010 and are available online: J Am Coll Cardiol (doi:10.1016/j.jacc.2010.03.009).

This is the relevant information from the label for Warfarin: ”

The dose of COUMADIN must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by:

Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and
Genetic factors (CYP2C9 and VKORC1 genotypes).

Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients.

The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 of the Prescribing Information describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.”

Some physians argue that this test should not routinely obtained and that only if it is “available” should it play a role in dose modification. I do not find this a credible interpretation of the Prescribing Information langauge. Considering that the label of Warfarin includes CYP2c9 testing, this test should be considered medically necessary.

For the Professional version see here

FAP and AFAP testing: Genetic colon cancer

M Levin, MD — Fri, 24 Aug 2012 13:48:34 +0000

A small proportion of colon and rectal cancers arise in individuals who have genetic mutations. Familial Adenomatous Polyposis(FAP) and AFAP are autosomal dominant disorders with 50% risk of inheritance and about 75–80% of individuals with these conditions have an affected parent. Autosomal dominant inheritance means that an offspring of an affected individual has a 50% risk of inheriting the altered APC gene.
Adenomas develop in approximately half of all patients with FAP by age 15, and in 95% by age 35. Without intervention, most individuals with FAP will develop colon or rectal cancer by the fourth decade of life. Thus, screening and intervention for at-risk persons is critical and typically begins at puberty (National Comprehensive Cancer Network® [NCCN®], 2012). AFAP is an attenuated variety of FAP. Evidence in the published, peer-reviewed scientific literature indicates that genetic testing for mutations in the APC gene is appropriate for a specific subset of individuals who have been identified as at high-risk for FAP or AFAP. Among the specialty organizations that have recognized the role of FAP and AFAP genetic testing are the American Gastroenterological Association (AGA), American College of Medical Genetics (ACMG), NCCN and National Cancer Institute (NCI). It is generally accepted that genetic testing for FAP and AFAP is appropriate for the following purposes:
• to confirm the diagnosis of FAP and AFAP in an affected patient
• to provide predictive testing for at-risk relatives of AFAP and FAP-affected patients with known APC gene mutation.
MYH-Associated Polyposis (MAP), also known as MUTYH-associated polyposis, is a recently described syndrome that is related to FAP and that is also characterized by adenomatous polyps. It is, however, an autosomal-recessive syndrome, in which half of the affected individuals are carriers of the disease but are not affected, unless they receive one gene from each parent.

American College of Medical Genetics (ACMG) and the American Society of Human Genetics (ASHG) and American Gastroenterological Association (AGA) also offer guidelines. For genetic counseling and testing for adenomatous polyposis syndromes, including FAP, and AFAP, the guidelines include the following (NCCN, 2012):
• FAP Inclusion criteria include:
Presence of over 100 polyps, or fewer polyps at younger ages, especially in family known to have FAP
Autosomal dominant inheritance
Possible associated additional findings, including:
o Congenital hypertrophy of retinal pigment epithelium (CHRPE)
o Osteomas, supernumerary teeth, odontomas
o Desmoids, epidermoid cysts
o Duodenal and other small bowel adenomas
o Gastric fundic(body) gland polyps
increased risk of medulobastoma, papillary carcinoma of the thyroid (<2%) or hepatobalstoma (usually ?age 5 years)
Pancreatic cancers (<1%)
Gastric cancers (<1%)
• AFAP inclusion criteria include:
Fewer than 100 adenomas (range 0 – >1000) (average of 30 polyps)
Frequent right-sided distribution of polyps
Adenomas and cancers at age older than classic FAP (i.e., mean cancer age greater than 50)
Upper GI findings and thyroid cancer risk is similar to classic FAP
?Other extraintestinal manifestations, including CHRPE and desmoids are rare
• If personal history is positive, then refer to genetic screening
• If family mutation is known, then refer at-risk family members to genetic screening
For genetic counseling and testing for MAP, the guidelines include the following (NCCN, 2012):
• MAP inclusion criteria include:

Polyposis or colon cancers consistent with autosomal recessive (i.e., parents unaffected, siblings affected)
Fewer than 100 adenomas (range 0–100s and uncommonly >1000)
Adenomas and colorectal cancer at age older than classical FAP (median age >50)
Duodenal adenomas are uncommon
Attenuated polyposis with negative APC gene mutation

• If personal history is positive, then refer to genetic screening
• Testing for APC gene mutations usually precedes testing for MYH mutations, except in families in which only siblings are affected
• Recommend genetic counseling and testing for germ line MYH mutations for siblings of affected patients
• If family mutation is known, then refer at-risk family members to genetic screening

Read the Professional version here.

Cancer Treatment Today » Genetics

Genetic test for Coumadin

FAP and AFAP testing: Genetic colon cancer