A disquieting moment: Two steps backwards?


Just about all of us attending the San Antonio Breast Cancer Symposium were disappointed and puzzled by two negative studies that went counter to all the early clinical data and biological theories in two important areas. While we recognize that this can sometimes be the normal course of science, it is never what we expect when we attend a meeting amid all the buzz about the latest news.The first was in the area of personalized medicine--more specifically, the field called pharmacogenomics, which refers to the analysis of gene variants in drug metabolism enzymes to customize recommendations for specific drugs and doses. We all inherit different versions of the gene that encodes an enzyme called CYP2D6, which metabolizes the hormonal therapy tamoxifen into a more active form called endoxifen. While preliminary studies showed that those who inherit a low activity version of this gene might have a higher risk of recurrence or progression on tamoxifen, it appeared that a new method to steer patients to the right therapy might be emerging. However, these early results were on smaller groups of patients. More recent and much larger updates presented on Thursday showed no difference at all based on CYP2D6 genotype, even though tests are already commercially available and used by some oncologists. The consensus from the presenters, including the commentator, Dr. Matthew Goetz from Mayo Clinic, (one of the original investigators to observe differences in clinical outcomes), is that for now, doctors should discuss the controversy with patients, but not use CYP2D6 testing routinely to make decisions about tamoxifen. However, it is still recommended that drugs that inhibit CYP2D6, notably certain anti-depressants, should be avoided in patients taking tamoxifen. This is not really a big step backwards for patients because it doesn't necessarily take any benefits or options away. But it is an unexpected turn in the road where all the pieces of the puzzle were starting to fall together, only to be contradicted for the moment.Another negative confirmation, however, was really a setback. Every indication was that bisphosphonates (a class of drugs used to protect the bone from both osteoporosis and bone metastases) might also prevent metastases. Several studies had suggested this earlier. In a smaller study of premenopausal patients receiving hormonal therapy, the drug Zometa had already been shown to lower the risk of recurrence. The supposition was that it made the bone a less fertile ground for breast cancer cells to colonize and use it as a springboard to metastasize elsewhere. But after a long anticipated wait, a much larger study yielded absolutely no difference in patients who received Zometa compared with those who did not. A secondary analysis hinted that in postmenopausal patients, there might be a benefit, but this was not statistically significant and no recommendations can be made at this time to use Zometa as a way to further reduce recurrence risk above what chemotherapy and hormonal therapy can achieve. A large North American study was recently completed, but the results of this one are not expected for several years. The good news is that these studies took longer to analyze because fewer women are recurring after early-stage breast cancer than ever before. Still, we would like to get this down to zero and still have a ways to go. Progress is just never linear, but even negative data helps us create better experiments and trials for the future.

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