Routine mutational and plasma level testing: The time has come

By Norman Scherzer
LRG Executive Director

Mutational Testing

The case for routine mutational testing of GIST patients at diagnosis seems compelling to the patient community and to a select number of GIST specialists who have begun integrating this into their medical practice. The relationships between mutational status and the treatment of GIST with imatinib, sunitinib and other drugs continue to be documented. It seems quite clear, for example, that exon 11 patients respond better to imatinib and that exon 9 patients respond better to sunitinib; furthermore, that exon 9 patients treated with imatinib respond better to higher doses. Despite this growing body of knowledge and despite the availability of mutational testing at a small but increasing number of laboratories, most GIST patients still have not had this test performed and most treatment facilities still do not include mutational testing as a routine part of patient evaluation.

Mutational testing for GIST patients was first demonstrated on a research basis in 2000 and eight years later it primarily remains there.

For GIST patients with prior surgery (the majority of such patients), the test requires that a tissue sample on file at the hospital where the surgery was performed be shipped to one of the laboratories performing such a test (Please go to www.liferaftgroup.org/mut_testing.html for more information on this process).

Plasma Testing

The case for routine plasma level testing has been somewhat slower in developing a clear rationale, with research in CML leading the way. The past year hasseen a few research papers suggesting that there may be a relationship between the trough levels of imatinib and clinical benefit for GIST, at least with exon 11 patients. There is some suggestion that GIST patients with trough levels above 1100ng/ml may have longer progression-free survival times than those below that level.

In June 2008 an international gathering of GIST patient advocacy group representatives unanimously adopted the Global GIST Patient Community Declaration calling for routine plasma level testing of GIST patients. In August 2008, a prominent US oncologist wrote to one of his patients that such testing for GIST patients was not necessary and that he would not adjust his patient’s dosage based upon the results of such a test. This represents a point of view we feel is not unique in the medical community. Why is there a disconnect between the patient advocates and the medical community?

I will let the medical community speak for itself by inviting them to respond in a future LRG Newsletter. For our part, the rationale is based upon two foundations.

Research: Plasma level data would help research the issue of imatinib dosage levels and resolve the difference between the recent LRG data, which showed a relationship between higher imatinib levels and overall survival, and that of the formal MetaGIST study, which showed that there was no such relationship. Such data would also help explain why some GIST patients with lower imatinib doses continue to do well and why some with higher imatinib doses do not, by addressing whether it is the plasma level of imatinib rather than the dosage level that is the key determinant to overall survival.

Clinical Practice: Although we do not yet know enough about imatinib plasma levels to make clinical decisions based entirely upon such test results, I would submit that knowledge of plasma levels is an important piece of information for patient management and that integrating such a test into routine clinical practice should start immediately. At a minimum, it would be helpful for every patient to have baseline data on where their plasma levels are now. This would be particularly useful for newly diagnosed patients beginning imatinib.

Continuing to perform such a test on a routine basis might well provide the clinician with useful information even though we have not yet established definitive reference test levels related to long term survival. Consider for example a patient on 400mg of imatinib whose trough levels fall over time from an initial 1600ng/ml to 400ng/ml. Might this not be a cause for concern that the dosage level is too low or perhaps that the patient may not be taking all their medication? Consider another example of a patient on a higher dose of imatinib struggling with unacceptable sideeffects, whose trough levels remain constant at 2400ng/ml. Might this not provide a supporting rationale for lowering the dosage but continuing to monitor the plasma levels to ensure that they do not drop to alarmingly low levels?

Admittedly, the logistics of ordering a plasma level test are somewhat difficult. They require taking the blood test within a narrow time period (22 to 26 hours after the last time the patient took imatinib) and shipping the blood, after centrifuging it, to a specific laboratory. However, the actual procedure of a blood test requires little imposition upon the patient or the physician. The fact that it can be done free of charge by Avantix Laboratories can only add to the rationale.

The patient community can no longer tolerate the unacceptable time gaps between the development of laboratory tests and their utilization in standard clinical practice. The case for routine mutational testing is compelling. The case for routine plasma level testing is sufficiently developed that it too should become standard clinical practice. Combined with routine mutation status testing this would lay the groundwork for individualizing patient treatment. Imagine the embarrassment of the medical community to have ignored for years basic tools that could have saved lives.