Short summary

We aim to substantially reduce the risk of serious adverse reactions in patients receiving 5-fluorouracil (5-FU) for gastrointestinal cancer or breast cancer. Our project implements personalised treatment in everyday cancer treatment by genotyping for variants that confer a reduced metabolism, and increased risk of adverse reactions, of 5-FU, and adjusting dose accordingly.

This project may serve as a proof-of-concept for implementation of personalized medicine in everyday cancer treatment.

Rationale

With this proposal, we will immediately bring personalized medicine and pharmacogenomics to the patient in an everyday clinical cancer treatment setting.

Background

The mapping of human genome 15 years ago posed a great promise of personalizing patient treatment. Despite considerable resources and efforts allocated, it has proven difficult to implement pharmacogenomics research findings into everyday clinical practice to the benefit of patients. 5-fluorouracil (and its prodrugs capecitabin and S1), are chemotherapeutic mainstays in the treatment of gastrointestinal cancers and breast cancer. 10-20% of patients develop severe adverse reactions such as immunosuppression or severe enteritis which substantially prolongs treatment and suffering. These drugs are metabolized by the dihydropyrimidin dehydrogenase enzyme. Genetic variants in the encoding DPYD gene confer reduced activity and an increased risk of severe toxicity.

Aim

To reduce the overall incidence of severe adverse reactions to chemotherapy regimens containing 5-FU, capecitabine or S1 in an unselected population of gastrointestinal cancer or breast cancer patients through pre-emptive DPYD genotyping.

Design

We will conduct an open clinical trial using historic controls. As a claim of equipoise cannot be made, a randomized trial (randomizing patients to genotype assisted dose versus usual practice) is unethical. We will implement pre-emptive genotype testing of about 1000 consecutive patients subject to 5-FU, capecitabine, or S1 treatment for gastrointestinal cancer or breast cancer. We will use a historic control group of about 2000 consecutive similar patients.

Clinical Impact

This proposal will significantly advance implementation of personalized medicine in Denmark, and will have immediate impact within an everyday clinical setting for cancer patients. We will systematically address the clinical efficacy and cost-effectiveness of personalized medicine within the frame of the proposal.

Description of the cohort

DPYD-genotype

All gastrointestinal or breast cancer patients elidible for treatment with drugs containing 5-fluorouracil(Capecitabine, S-1) at Odense University Hospital and Hospital of Southern Jutland.

Controls

Historic controls will be sampled from the same population as listed above.

Data and biological material

From biobank(blood):

Phenotype test (uracil/dihydrouracil)

Blood for future unspecified research  

Data from electronic health records:

Age / sex

Chronic diseases 

5-FU related toxicity / adverse events

Cancer diagnosis / stage

Dose alterations

Hospitalizations

Blood test results

Use of Prescription drugs

Disease progression

DPYD genotype

Vital parameters 

Collaborating researchers and departments

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

• Professor Per Damkier, MD, PhD
• PhD-student Niels Herluf Paulsen MD,
• Clinical lector Troels Bergmann MD, PhD

Department of Oncology, Odense University Hospital

• Professor Per Pfeiffer MD, PhD
• Profressor Marianne Ewertz MD, Dr.med

Department of Oncology, Hospital of Southern Jutland

• Consultant Martin Jensen, MD