April 2013, Vol 2, No 2

← Back to Issue

Comprehensive Gene Analysis Allows for Personalization of 5-FU to Reduce Risk of Toxicity

Wayne Kuznar

Uncategorized

About 3% to 5% of the general population is believed to have a mutation in the gene that encodes a major 5-fluorouracil (5-FU) metabolizing enzyme. This mutation can extend the half-life of 5-FU, leading to increased plasma concentrations and potential toxicities, said Colleen Rock, PharmD, PhD, at the Hematology/Oncology Pharmacy Association 9th Annual Conference.

Comprehensive analysis of the gene – DPYD – can be used to personalize a patient’s 5-FU/capecitabine therapy, she said.

The rate-limiting enzyme in the metabolism of 5-FU (and its oral prodrug capecitabine) is dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene. “A mutation in the gene can lead to drug accumulation; approximately 80% of 5-FU is rapidly metabolized by DPYD in the liver,” said Rock, clinical research associate at Myriad Genetic Laboratories, Inc, Salt Lake City, Utah. “If there’s a mutation that affects the protein function, it’s not going to be metabolized. There’s going to be accumulation, and this can lead to toxicity.”

Analyzing the DPYD gene “can allow us to decide whether to potentially reduce the dose of 5-FU in a patient or even switch to a different drug,” she said.

The data she presented were from an analysis of full gene sequencing test results from 3083 patients. DPYD analysis was performed by polymerase chain reaction and DNA sequencing. Genetic variants were tested using multiple variant classification techniques, including comparison with a consensus wild-type DPYD sequence.

“Because of the large number of patients included in this analysis, we have good information regarding prevalence, and found that the prevalence for the common DPYD mutations in the testing population is 7.3%,” said Rock. The 3 common high-risk mutations were IVS14+1G>A (52.0%), D949V (40.5%), and 1560S (7.5%).

Full sequence analysis of the gene allowed for detection of a unique variant – E412E – that has been linked with a deleterious mutation in DPYD in some cases (N=12). “When we take the E412E variant into account, along with the common mutations, the potential exists for an almost 11% prevalence of gene mutation,” she said. “These patients who have a mutation are at risk for toxicity. Only full gene sequencing allows for identification of both common and novel mutations that may be associated with 5-FU toxicity.”

In a subset of 24 patients who were tested for DPYD mutations in response to an elevated 5-FU plasma level, gene variants were identified in 7 of the 24. In this population, the E412E variant occurred with similar frequency as that of the common high-risk mutations.

DPYD mutations were found with greater frequency in patients who suffered a greater number of 5-FU toxicities prior to DPYD gene testing. While the majority of patients were tested after experiencing at least one 5-FU toxicity, among those without pretest toxicities, the prevalence of DPYD mutations was 4.7%, which increased to 31.6% in patients with 4 toxicities.
Among the 5-FU toxicities, the prevalence of mutations (18.5%) was greatest for hematopoietic events, followed by hand-foot syndrome and stomatitis (12.6% each).

Most providers choose to submit a sample for testing after a 5-FU toxicity has occurred, said Rock. “I think that the preference would be to prevent toxicities and therefore test ahead of time, including for the E412E mutation,” she said.

The prevalence of mutations also varied by ancestry, with mutations most common among European and Latin American patients.

Uncategorized - April 22, 2013

Targeted Therapies Added to Docetaxel Do Not Extend Survival in Metastatic Prostate Cancer

The latest in a string of failed trials of targeted therapies added to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) were presented at the 2013 Genitourinary Cancers Symposium. No survival benefit was observed with the addition of aflibercept to docetaxel/prednisone in the VENICE trial1 or with the addition of dasatinib [ Read More ]

Uncategorized - April 22, 2013

The RomneyCare Bill Comes Due

The health reform that Mitt Romney passed in 2006 in Massachusetts presaged President Obama’s, and its results are showing what we can expect nationwide. The latest warning comes in a huge new tax increase proposed by Governor Deval Patrick. The second-term Democrat followed his party’s recent habit and proposed an [ Read More ]