- Dr. C. Michael Gibson, Duke University

Dr. Gibson and Dr. Kirtane from Duke University reconsider genetic testing for CYP2C19 based on the GIFT sub-study of GRAVITAS presented last week at ACC. The study clearly showed that poor metabolizers (CYP2C19 *2 homozygotes) were at high risk of treatment failure and that dose adjustment showed response improvement in heterozygotes.

Dr. C. Michael Gibson: I was not one that defended the FDA’s decision about genetic testing and recommendations, but now, you know, you kind of wonder, should you be doing some testing to identify these (2C19) homozygotes?

Dr Ajay Kirtane: I was completely in same camp as you were at that time and it seemed that it was premature to release a statement like that, but after assessing this and realizing that…I’m wondering if maybe we should spend more effort trying to find these non responders for the homozygous gene.

See their six minute video here: http://www.vimeo.com/22008430
See details of the study at: http://www.theheart.org/article/1208199.do

Odds ratio (95% CI) for platelet reactivity above 230 PRU at 30 days according to CYP2C19*2 carrier status

Adjusted hazard ratios for CV death, MI, or stent thrombosis according to CYP2C19 genotype

If you’ve been sitting on the fence regarding whether to implement this simple genetic test please take a moment to consider this month’s GIFT findings, the JAMA Mega meta-analysis from Oct 2010 and the FDA black box warning from March 2010.

Call Genelex today at 800-837-8362 x 2851 to order our simple buccal swab or blood test kits.  Testing is covered 70% of the time in full by private insurance.  Medicare covers Plavix testing 100%.  It’s our goal to help ensure safe and accurate prescribing through actionable science.

The tragic deaths described in these stories seem largely avoidable, given what we know about drug interactions, pharmacogenetics and the DNA testing and software tools we have for managing complex medication regimens. Many of the drug interaction described in this article are well- known. Many more will be predicted only by GeneMedRx. Physicians are also generally unaware of the extent to which these interactions can be made more severe or treatment can fail according to DNA status of the CYPs for which they can order testing.  It’s frustrating that medical practice is so slow to use the knowledge and tools available to solve these problems, but every year, and now it seems like every month we get closer. I’m sending an email to the reporters who did this story to see if I can get the exact med regimens of these soldiers so we can put them into GeneMedRx and provide the reports to some of the individuals quoted in this story in the hope that we can help solve this problem.

- Howard Coleman, Genelex CEO

I have to question the conclusions drawn in this study. The number of patients found to have variant alleles does not compute. Of the 5059 patients genotyped, only 25.5% had a variant allele including those patients the authors categorized as unknown. This is the lowest percentage in any large clopidogrel CYP2C19 study to date as outlined in the table below. Some of these studies also excluded patients of Asian and African descent with a higher number of variations so that doesn’t explain the discrepancy. This naturally leads one to question why the tested population had a lower percentage of patients with variants. Patients in the Active A and Cure trials were originally enrolled four to ten years ago. It is likely the results of this study are skewed because a number of patients from the original studies with CYP2C19 variations were given clopidogrel, and failed to respond. Numerous studies and a meta-analysis have confirmed that reduced CYP2C19 function is linked to excess mortality, so many non-responders were eliminated from the patient population. If anything, this study confirms that patients with variant alleles are at increased risk, otherwise where did they go?

His response was as follows:

Thank you for your interest in our manuscript.  We believe our allele frequencies to be in line with other reports given the expected random fluctuation in frequency estimates.  For example, the very large PLATO genetics study (Lancet 2010) reported a frequency of ~26% for loss-of-function carriers.  Estimates are likely to fluctuate in smaller studies because of the play of chance.  CURE and ACTIVE are double-blind randomized prospective studies and our analysis was performed on a intent-to-treat basis.  We therefore feel unlikely that selective censoring of loss-of-function carriers explain these results.

My thoughts on his response:

Actaully, the Plato study reported a frequency of 26.96% for loss-of-function carriers- lower than any other large-scale study to date, but still much higher than 25.55%.

Are there any biostatiticians or other experts reading this or someone that can tell me what reasonable ranges are? In a purely Caucasion population, I would expect a range from 27-29%, higher if other ethnicities were included in the study. I am not saying I am right- I am just wondering if any experts out there can tell me what a reasonable variance would be.

Just on the heels of this major announcement, Medco and Mayo presented study findings at the ACC today proving the cost effectiveness of warfarin genotyping. The study found that hospitalization rates were 31% lower when genetic test results were incorporated into warfarin management. See https://www.medcoresearch.com/community/pharmacogenomics/warfarin for more details.

The FDA should be applauded for this black box warning, and Medco and Mayo should be commended for their important research. Now it’s time to move beyond the silo mentality and start realizing the full benefits of personalized medicine. “Properly” prescribed medications kill twice as many Americans as car accidents. This is often due to genetic factors; 59% of medications most often cited in adverse drug reactions (ADR) studies are drugs processed by pathways whose levels vary widely genetically- like Plavix and Warfarin. We put airbags and seatbelts in cars, but we won’t take less expensive measures to protect people from ADRs. A simple, fairly inexpensive DNA test that examined 2C19 (the pathway for Plavix and 10% of other meds), 2C9 (the main pathway for warfarin and another 10% of meds), and 2D6 (the main pathway for most pain killer and 25% of meds) could dramatically improve the safety of prescribing. It’s time to move past one size fits all prescribing, and the Plavix warning and Medco/Mayo study are two serious steps in the right direction!

Ten percent of women have a gene variation which prevents them from producing the enzyme CYP2D6 which is essential for tamoxifen effectiveness. In another thirty-five percent with a gene variation the production of this enzyme is reduced which impedes the effectiveness of tamoxifen. A study published this month in JAMA, the Journal of the American Medical Association, reported that these classes of patients had, respectively, a 29% and 20.9% recurrence rate compared to 14.9% for patients without this gene variation.

“We need to remember that these aren’t just numbers, these are women we care about. These are our sisters, and mothers, and friends,” said Howard Coleman Genelex Corporation’s CEO. “We need to start using the tools we have available to ensure that their cancer treatment is as successful as possible.”

National Foundation of Cancer Research (NFCR) has a long history of funding innovative research in the fight against cancer. NFCR is also committed to making sure new technologies are reaching patients who need them. NFCR is working with Genelex to increase awareness of factors, such as this gene variation, which diminish the effectiveness of tamoxifen. NFCR and Genelex also are promoting awareness of alternative treatments for patients who do not respond well to tamoxifen.

“It takes time to move a technology from bench to bedside. When it comes to DNA testing to determine if breast cancer patients are likely to benefit from tamoxifen, that wait needs to end,” stated NFCR President Franklin C. Salisbury, Jr.

Even in patients who do not have this gene variation, the effectiveness of tamoxifen may be impeded inadvertently. Numerous studies have shown that interactions with many prescription medicines, over-the-counter medicines, and even herbal remedies can reduce tamoxifen effectiveness.

Genelex Corporation offers Tamoxitest which provides an assessment of both risks to tamoxifen effectiveness. Interpretive software included with results alerts patients and their physicians if tamoxifen benefit is at risk as a result either of the gene variation discussed above or interactions with medicines and herbal remedies.

Los Angeles oncologist Dr. Michael Benjamin, MD is one of the first physicians to embrace this technology.  “The Genelex gene profiling technology is a powerful tool to help my patients.  With tamoxifen testing, we can appropriately individualize treatment based on patients’ ability to process the medicine.”

Benjamin regularly advises his patients to take Tamoxitest. “Genelex tamoxifen testing helps me be smarter about who I treat with tamoxifen, and why.  I can take the discoveries made in their labs right to the patient’s bedside,” states Benjamin. “I see it as the wave of the future in medicine.”

Maura, a breast cancer patient, says that she ordered Tamoxitest after she was diagnosed.  Her healthcare professionals did not discuss Tamoxitest with her. Rather, Maura learned about this valuable test on the Internet. Found to be an intermediate metabolizer, Maura and her doctor opened a dialogue about her dose of tamoxifen.  “It was worth the information – and peace of mind – I received,” she concluded.  Most insurance companies cover the test.

Breast cancer patients and healthcare providers can learn more about Tamoxitest at www.Tamoxitest.com. 

The National Foundation for Cancer Research’s website is www.NFCR.org.

Dr. Michael Benjamin’s website is www.interactMD.com

Reporters seeking comment, or an interview, may call Kristine Ashcraft, Genelex Corporation, at (206) 826-1957 or Erin Chen, National Foundation of Cancer Research at  (301) 961-9116.

The conclusion:
Recurrence Rates:
14.9% for extensive metabolizers
20.9% for intermediate metabolizers
29.0% for poor metabolizers

This means that Extensive Metabolizers will get the same preventative outcome from tamoxifen as much more expensive aromatase inhibitor that have the added risk of potential bone and joint effects.

My take, Tamoxitest CYP2D6 testing is ready for prime time. It’s a win-win for patient, physicians, and payers – reduced costs and improved outcomes!

Jessica Oesterheld, MD is one of the authors of the best selling Clinical Manual of Drug Interaction Principles for Medical Practice. After analyzing the purported medication list she noted that “many of the concentrations of these drugs would have been dangerously increased.” Propofol often causes accidental death in recreational users. Interactions between propofol and many of the drugs Jackson is alleged to have been taking, such as Paxil, Zoloft and the opioid pain medicines Demerol, Vicodin, and Dilaudid, increase the potential dangers of those drugs.

Dr. Oesterheld’s experience with adverse drug reactions led her to collaborate with Dr. Robert Patterson, a fellow clinical psychiatrist and computer programmer. Together they developed GeneMedRx, a tool for analyzing the cumulative effect of the many factors leading to adverse drug reactions including prescription drugs, over-the-counter medicines, foods, herbal preparations, recreational drugs, and genetics that are missed by other drug interaction programs. The dangers inherent in Michael Jackson’s purported drug regimen would have been even greater for individuals with a positive DNA drug sensitivity test who comprise more than half of the population. DNA Drug Sensitivity Testing detects the up to 1000-fold person-to-person differences in drug processing capacity. You can see the “hidden” interactions GeneMedRx predicts at www.HealthandDNA.com/Jackson.

Michale Jackson's purported medication list

Genelex Corporation, Seattle, Washington is a DNA testing laboratory dedicated to reducing the high levels of morbidity and mortality that result from adverse drug reactions by personalizing medicine with the combination of DNA Drug Sensitivity Testing and GeneMedRx software.

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?
Laika B, Leucht S, Heres S, Steimer W.

Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, München, Germany.

The cytochrome P450 2D6 (CYP2D6) isoenzyme metabolizes about 25% of clinically used drugs. The impact of CYP2D6 metabolizer status on therapeutic outcome was assessed in 365 psychiatric in-patients treated with neuroleptics or antidepressants. Length of hospitalization and response onset were prolonged for patients receiving CYP2D6 drugs.
Intermediate metabolizers (IMs) receiving CYP2D6 doses above the population median had more side effects after 4 weeks than extensive metabolizers with above-median doses (9/13, 69% vs 4/23, 17%, P=0.003), than IMs with below-median doses (5/22, 23%, P=0.012) and IMs with other medication (24/84, 29%, P=0.009). The Clinical Global Impression scale response was lower for IMs treated with CYP2D6 drugs (3/42, 7%) than for IMs with other medication (21/84, 25%, P=0.017) probably due to increased side effects.
Identification of IM status (38% of study population) may help to reduce side effects and length/cost of hospitalization. Thus, not only poor and ultrarapid metabolizer but also IMs may benefit from CYP2D6 genotyping.
This is of paramount interest since it greatly improves cost/benefit estimations for pretreatment CYP2D6 screening.The Pharmacogenomics Journal advance online publication, 19 May 2009; doi:10.1038 /tpj.2009.23 .

PMID: 19451914