Real world theragenomics and personalised medicine
Last Updated on June 26, 2022 by Joseph Gut – thasso
June 23, 2022 – Expansion of pharmacogenetics education agreed as part of lawsuit settlement. This has just been the headline objective of one of the latest blogs from the PharmGKB blogspot, an NIH-funded resource (database) that provides information about how human genetic variation affects responses of individual patients to medications.
The post talks about the outcome of a lawsuit settlement, in the State of Oregon in the USA, in which the fate of a patient played the central role. This patient, David, the husband of Madam Joanne McIntyre, died as a result of severe capecitabine toxicity. David carried an allelic variant in the DPYD gene, which encodes the DPD enzyme. The DPD enzyme is involved in metabolism of fluoropyrimidine drugs, such as Xeloda (Capecitabine), HCFU (Carmofur), Doxifluridine, Adrucil (Fluorouracil), and Tegafur. Some genetic variants in the DPYD gene, such as those that David carried, can inactivate the DPD enzyme, leading to DPD deficiency. Patients with DPD deficiency are unable to properly metabolize fluoropyrimidine drugs, including Xeloda (Capecitabine), and are at risk of experiencing severe, if not fatal, drug toxicity. In fact, the FDA’s drug label carries a very prominent warning in it’s “Warning and Precaution” section to that effect, saying that patients with DPYD genetic defects (variations) be excluded from therapy with Xeloda (Capecitabine) which was approved by the FDA in 1998 as a nucleoside metabolic inhibitor with antineoplastic activity indicated for adjuvant colon cancer, metastatic colorectal cancer, and metastatic breast cancer.
In terms of real world theragenomic and personalized medicine, apparently the patient David had been genetically tested and found DPYP gene deficient. And apparently, the treating organization, a clinic at the Oregon Health & Science University (OHSU), was aware of this findings, yet did not stop to treat patient David with Xeloda (Capecitabine), despite all the qualified drug warnings about the serious risks for patient with this condition. This we can deduce from the lawsuit settlement mentioned above. In effect, David McIntyre was diagnosed with bile duct cancer in September 2018 and sought treatment from OHSU. But because of the genetic condition of
DPYD-deficiency that affects as many as 8% of people, his body couldn’t process one (i.e., Xeloda (Capecitabine) of the chemotherapy drugs he received from the hospital. He became extremely ill, with vomiting, a rash and diarrhea. Sadly, by the time doctors gave him the antidote, it was too late for it to be effective. The 78-year-old patient died on December 12, 2018. But, as Joanne McIntyre, his widow, learned, David didn’t have to die. Not only are there genetic tests for the DPYP-deficiency condition, there are also clinical guidances in place on how to reverse a unwanted reaction to the drug Xeloda (Capecitabine) if the patient is showing symptoms.
Following and applying such measures of theragenomic and personalized medicine could nowadays be expected, particularly in the clinic of an University. Apparently not in this case; seemingly the University never informed the patient about his genetic condition, that it can be tested for, nor did the treating physicians give the patient the antidote in time, according to the lawsuit.
Outraged and grieving, Joanne McIntyre and her attorney, James Huegli, filed a wrongful death suit against OHSU in Multnomah County Circuit Court in 2019. OHSU denied fault in the case, saying that it has followed, and continues to follow, national cancer and evidence-based medicine set forth by national expert consensus in the field. In the settlement outcome reach between the parties, the Oregon Health & Science University (OHSU) conceded to the promise to change an aspect of its cancer treatment and pay out $1 million to settle the lawsuit claiming the university’s negligence killed a cancer patient. Although OHSU said testing for the genetic condition isn’t standard practice, the university is nonetheless going to include education on the condition in its Oncology Fellowship program. It is also going to create a guide that describes the condition and how to identify symptoms of a toxic reaction to the chemotherapy drug.
This latter statement is rather astonishing, in that today (in 2022) and for quite some time by now, testing for genetic conditions that may seriously, if not fatally, affect a patients reaction to a given drug should be established standard clinical practice. Over the last couple of years, a enormous amount of knowledge has been developed in order to be used in personalized (precise, theragenomic, targeted, you name it) medicine to optimise the effect of therapies of patients with particular genetic constellations and to avoid serious, if not fatal events of such therapies. Resources are there: Tables of Biomarkers at FDA, Allelle-specific guideline information by the CPIC, Clinical Guidelines at PharmGKB, etc., etc.
Taking into account all these existing resources and the accompanying analysis methods to determine the possible, prospective, and/or foreseeable reaction of an individual patient facing one of the sometimes more than intriguing therapy regimens, it is astonishing and unforgivable that in the clinical setting, individual patients may still be treated inadequately, badly informed, and put at fatal therapy risks.
See here a short sequence on Xeloda (Capecitabine):
Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
Hello Dr. Gutt – Thanks so much for your quick reply and support of my efforts to make patient safety a priority through PGx. Interest in the subject is definitely on the rise in the US and I do believe that my lawsuit was one of the contributing factors. But more than that, the death of a world-renowned physician in Toronto, Canada and the Canadian Broadcast Company interview yesterday will do much to keep the subject alive and add more pressure to make changes to the SOC. Here’s a link to the broadcast video: https://www.cbc.ca/player/play/2287162435583 Dr. Kapoor’s brothers are now members of my advocacy group. I would love to introduce you to AUDT at one of our monthly Zoom meetings to share your experiences with DPD enzyme deficiency. For more information about our advocacy, visit our website at http://www.test4dpd.org
Please feel free to contact us through our AUDT Facebook page or our website if that is something you would like to do. It would truly be an honor to have you as our guest!
Joanne
P.S. Can you tell me which country you are located in?
Dear Dr. Gut – As the widow of the patient you write about in this article, I want to personally thank you for advocating for this life-saving test prior to the initiation of the chemotherapy Zeloda/capecitabine and 5-FU. Following my husband’s death, I was frankly in disbelief that preemptive testing is not yet the standard of care in the United States and began my research, not only for the lawsuit, but to find others in the US who had lost a family member due to a lack of upfront testing. Fast forward to 5 years later and we are now a non-profit called AUDT – Advocating for Universal DPD/DPYD Testing. http://www.test4dpd.org We attend the ASCO conferences to bring attention to this life-saving issue and spread the word through direct contact with medical professionals and family members who, like me, look for answers to their loved-ones deaths. Patient Safety is our #1 concern, and the FDA absolutely must update their policy to mandate testing. Thank you so much for writing about the critically important subject! Joanne McIntyre
Thanks for your comment. First of all: my heartfelt condolences on the loss of your husband. Secondly: my entire scientific life was aimed at prospectively identifying serious, fatal side effects of medications and excluding beforehqnd affected patients from appropriate therapies through genetic testing. Unfortunately, the concept is not yet widely implemented.Thirdly, I congratulate you for your efforts to address the problem, at least for the DPD/DPYD environment and its medications. Thank you.
Thank you for your answers and invitation to join you and contribute qt some point to AUDT. I shall come back on that on a later time. In the meantime, I am from Switzerland, living in France, part-time teaching at the University of Basel (Switzerland), and having done in the past some 5 years research at Stanford University.