Update from ASCO: Personalizing breast cancer treatment

At ASCO's breast cancer oral abstract session, several findings that highlight this year's overall ASCO theme of personalized medicine were presented. It has been postulated that differences we inherit in genes that metabolize drugs might make a difference in how we react to them. Tamoxifen, a hormonal agent that has been used for three decades and shown to lower the risk of recurrence of hormone responsive breast, has recently been shown to be made more active when it is metabolized, or chemically changed into a more active compound called endoxifen. Studies have shown that those who inherited "weak" versions of the enzymes (particularly one called CYP2D6) that metabolize tamoxifen may have a higher risk of recurrence, presumably because they are not able to form the most active form of hormonal therapy. Certain drugs, like some antidepressants, can also inhibit this enzyme. Two large "real life" studies taken from pharmacy services that were used over a period of several years to look at the relationship between the outcomes of patients on tamoxifen and whether they also took drugs that inhibit CYP2D6 were presented. One showed more recurrences in those that took inhibiting drugs, while the other smaller study did not. So, the jury is still out as to whether this theory still holds water. However, since we know a lot about what drugs inhibit CYP2D6, it makes sense to avoid these when one is taking tamoxifen. The trickier question, not addressed in this study, is whether we should be doing gene testing on everyone for whom tamoxifen is recommended. These tests are already available, but we are not sure what to do. For example, in a premenopausal woman with early-stage estrogen receptor-positive cancer who has a "slow metabolizer" genetic variant of CYP2D, should we then block or remove the ovaries and use an aromatase inhibitor? This is a more complicated therapy with more potential side effects, but we do not yet have enough information to make this a standard of care.Other lectures in this session reviewed markers that predict recurrence risk and help with therapy decisions for early-stage breast cancer. Over the last few years, sophisticated tumor studies that measure the activity of multiple genes have been developed, but they have not been tested in what is called a prospective fashion. That is, the test is used for making a decision, and then the performance of the test is measured based on how patients actually do over time. One older biochemical test called uPA/PAI-1 (urokinase plasminogen activator and plasminogen activator inhibitor-1) developed over 10 years ago was actually tested in this fashion and the updated results do confirm that this test can segregate those at low versus higher risk of recurrence and also showed that the higher risk group benefited from chemotherapy compared to no treatment. This test never really caught on in the U.S. because of the inconvenience of requiring fresh tissue to be submitted. Now that more sophisticated multi-gene tests are used for prognostication, we are awaiting prospective trials which are years away from completion, but already these assays are being used based on retrospective data. The most important prerequisite to deciding what test to use is that the oncologist and the patient review how the risk/benefit analysis and subsequent treatment decisions would be affected the results of the test prior to ordering it.