By our very nature, people prefer "black & white" "yes or no" answers to questions. I don't know why, exactly. Perhaps it is simply a matter of gray answers making us think too much when we have to make a decision…such as whether to take a new drug. Gone are the days—or at least the public perception of the days—when a physician or drug company could say "take our new pill" for a given condition, which have been replaced with more cautionary statements of medicines helping a subset of patients under specific conditions given ambiguous criteria.
But wait. Genetic testing is the answer! "Have a gene, take a pill," they cried from on high. Do you have the HER2 marker? Then take our latest incarnation: Herceptin. Genetic testing provides clarity, security, and a general sense of pharmacologic euphoria. It's good for what ails—or might ail—you. Yes, genetic testing brings back those "black & white" feelings of…hold it, is that true black or dark charcoal?
Okay, perhaps I'm being a tad ridiculous, but it did seem that everyone was looking to genetic testing to clear up the confusion over which people should take what drugs. Recent research, however, is starting to show that there is no getting away from the grayness of the universe and that there is wiggle room even within the plus-minus world of genetic testing. Case in point is a study in the latest issue of the Journal of the National Cancer Institute on genetic markers of anticancer drug toxicity.
Researchers at the University of North Carolina examined the question of whether a specific genetic marker (UGT1A1*28) was predictive of toxicity in patients receiving Pfizer's colorectal cancer drug irinotecan (Camptosar). The question had been raised in late 2004 by an FDA advisory committee, which looked at earlier studies and advised Pfizer to amend the drug's product information to recommend patients with a UGT1A1*28/*28 genotype receive lower starting doses of irinotecan.
The UNC researchers examined nine studies of ten patient cohorts and found that although the UGT1A1*28/*28 genotype did correlate with toxicity in patients receiving moderate (150-250 mg/m2) or high (>250 mg/m2) irinotecan doses, there was no correlation for patients receiving low-dose (<150 mg/m2) drug. Thus, the FDA's advice to Pfizer seemed to be a case of putting the cart before the horse. Rather than base dosing on genetic testing results, they reasoned, any decision about genetic testing should be based on the patient's starting dose.
In this case, with the data it had at hand, the FDA tried to apply black & white constraints to a gray situation.
"There are so many treatment options for cancer patients that the more information we have about matching the right therapy to the patient, the better off we all are," said Dr. Richard Goldberg, study co-author and physician-in-chief of the North Carolina Cancer Hospital. "Studies like this one give oncologists the tools needed to take better care of patients while avoiding unnecessary tests and expenses."
The researchers are not suggesting that genetic testing is meaningless, but rather that the decision to test should not be taken as a given, particularly with rising healthcare costs. Instead, the decision should be made within the context of the available data, which must be re-evaluated regularly.
"This iterative example is likely to be the way forward for all/most of the pharmacogenetic examples," says Dr. Howard McLeod, lead author and director of the UNC Institute for Pharmacogenomics and Individualized Therapy. "The FDA does this for other aspects of a package insert, so no surprise if there is a multistep process for pharmacogenetic testing."
Living in a "gray" world is never easy—fraught as it is with unwelcome uncertainty—but it is our reality, no matter how much we would have it otherwise. Trying to convince ourselves that it can be any other way only delays the inevitable and sets everyone up for disappointment.