Can you please provide the readers of Expert Review of Molecular Diagnostics with an overview of your work?
We are currently working on diagnostic breath tests using suitably labeled stable isotope 13C substrates for evaluating polymorphic enzyme activities like CYP2D6, CYP2C19 and DPD.
What led you to this area of research?
At Cambridge Isotope Laboratories (CIL) I have been responsible for developing diagnostic breath tests with 13C-labeled compounds for the last 7 years. CIL is the largest manufacturer of stable isotopes in the world, including 13C, 15N, H2 and 18O, deuterium products. Otsuka Pharmaceutical, our parent company, has developed a cheaper infrared spectrophotometer. Our two spectrophotometers (UBiT® IR 300 and POCone™) were approved by the US FDA in 2002 and 2004, respectively. My job was to identify unmet medical diagnostic needs and design 13C substrates that would be able to identify patients with enzyme deficiencies.
What specific area of molecular diagnostics is evolving most rapidly & has the greatest demand?
Personalizing medication metabolized by polymorphic enzymes, such as CYP 2D6, 2C19, 1A2 and DPD is evolving most rapidly and has the greatest demand. Certain drugs may not have the desired efficacy or may cause toxicity as a result of variability in the enzyme activities in different human populations. It is therefore important to identify those patients who will not benefit from certain drugs that are metabolized by polymorphic enzymes.
What are the advantages of diagnostic breath tests over other potential diagnostic technologies?
These diagnostic breath tests are noninvasive, rapid (<1 h), easy to interpret, cheaper and since they are in vivo phenotype tests more accurate than the other tests. Most of the other technologies can predict the genotype but cannot accurately predict phenotype or drug–drug interactions.
Are there any limitations to diagnosis using breath tests?
One significant limitation is noncompliance with the required 6–8 h fasting conditions and alcohol restrictions (12 h) prior to the test will result in a false outcome. Breath tests on patients suffering from hypercapnia, cardiovascular disease or gastroparesis could lead to erroneous results.
I understand that the diagnostic breath tests aim to personalize treatment for disease. Are there other factors/variables that may impact the outcome of the breath test?
Genetics is the basis of variability in enzyme activities. However, genetic information alone will not be accurate enough to predict the phenotype. The diagnostic tests need to be rapid, easy to interpret for the physician to select the right drug at the right time at the correct dose to maximize efficacy and minimize toxicity.
What are the potential implications of such testing for the diagnosis & treatment of diseases such as cancer?
These tests will not diagnose or treat cancer but they will help in identifying the responders/nonresponders for various cancer drugs that have very narrow therapeutic indices. Examples include: the uracil breath test, which identifies patients that may suffer from 5-fluorouracil toxicity, a drug used in colorectal cancer; the pantoprazole breath test for the cancer drug cyclophosphamide used in the treatment of leukemia and lymphoma, and finally the dextromethorphan breath test used to identify responders and potential nonresponders to tamoxifen therapy, used in the treatment of breast cancer.
How widely used do you feel that personalized medicine will become given that, in the short term, it may appear to be less cost-effective?
The genetic tests need to come down in price and they also need to be linked to drug efficacy or toxicity in order to enable physicians to use them routinely in clinical practice. The phenotype tests, such as breath tests, will be more accurate, rapid, noninvasive and less costly. They could be used both at the bedside in a hospital or in a clinic setting.
Financial & competing interests disclosure
Anil Modak is currently involved in the development and commercialization of breath tests as diagnostic tests for various enzyme deficiencies and works for Cambridge Isotope Laboratories Inc., which is the manufacturer of the 13C substrates used for breath tests.
The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.