Tests to Detect Drug Resistance in Malignant Tumors. Should They Guide the Clinician’s Choice of Treatment?

Prof. Dr. R. Herrmann, Kantonsspital, Departement Innere Medizin, Abteilung Onkologie, Petersgraben 4, CH-4031 Basel (Switzerland) Resistance to cytostatic drug treatment is an all too well known phenomenon to a physician treating cancer patients. A wealth of information on multiple drug resistance (MDR) has been emerging over the past 15 years. We certainly have learned a lot about drug resistance mechanisms. Various complex systems seem to be involved, such as transmembrane transporter genes and proteins (MDR1 gene and p-glycoprotein), DNA repair mechanisms (topoisomerase II gene and its product) or cell detoxification processes related to glutathione and glutathione-S transferase with its many isoenzymes. Several reviews have covered this topic recently [1-4]. These MDR mechanisms are not unique to cancer but have also been observed in the treatment of infectious microorganisms. The paper by Volm and Mattern [5] in this issue compares two ways to test for drug resistance in non-small-cell lung cancer (NSCLC). On the one hand, there is a global test that detects drug resistance in vitro. On the other hand, tests are performed that measure the individual resistance mechanisms having been found to be associated with drug resistance. The authors find a good correlation between the in vitro short-term test and 4 out of the 6 individual parameters that were analyzed immunohistochemically. The reader may infer from these findings that clinical tumor response may be correlated to the results of an in vitro test or to results from immunohistochemical or molecular findings. So he may ask, ‘Are there currently tests avilable that tell me which patients do I have to treat or even which patient can profit from which drug?’ The best global test for drug resistance is certainly the assessment of tumor response in a patient given chemotherapy for his cancer. There is a variety of promising in vitro tests that may predict for tumor response such as the DiSC test [6], the MTT assay [7] or the assay described by Volm and Mattern. However, the clinical relevance of these tests is still debated and none of them has found its way into routine daily use. They may identify which tumor will respond to treatment, but they do not offer a satisfactory therapeutic alternative and herewith become prognostic factors similar to axillary node status in breast carcinoma or an elevated lactate dehydrogenase in the non-Hodgkin’s lymphomas, and everyone of us has seen enough of these risk factors lately. However, if we plan chemotherapy trials in NSCLC, we should implement such tests and then we could give an answer to the question whether it may be worthwhile to treat just the group with a specific pattern of in vitro sensitivity. But until now no such data is available and none of us would exclude a patient from treatment solely on the basis of the available global resistance tests.