IF I HAVE CANCER SHOULD I GET MY TUMOR GENOME SEQUENCED?
When genome sequencing first became available, many physicians avoided it citing concerns about its accuracy, the complexity of its interpretation, and its limited value in informing treatment decisions. These concerns still persist among some physicians today, but it is hard to imagine that these concerns will persist much longer. Aside from cost, there is nothing to lose by sequencing the tumor genome or at least the genes encoding known druggable targets and prognostic factors—one can, in fact, gain information. The following are possible outcomes of a cancer genome analysis with regard to treatment decisions:
- Nothing new will be learned
- The analysis will support the patient’s current course of treatment
- New information will be revealed, suggesting a new course of treatment
- Relevant information about an individual patient’s likely sensitivity to certain drugs will be revealed
- The information will be used for immunotherapy (see below).
We have found that (b) and (c) are frequent outcomes. The genome sequence might confirm that the patient is on the right course of treatment. For example, we sequenced the tumor DNA of a breast cancer patient whose tumor previously tested HER2-positive; the sequence revealed extra copies of the HER2 gene and confirmed that her current course of HER2-targeted therapy was indeed reasonable. Because initial screening may generate a false positive, the genome analysis provides helpful confirmatory evidence.
An example of scenario (c) might be a breast cancer patient who has completed several courses of chemotherapy, has met her lifetime allowable dose of anthracycline-based therapy (i.e., certain types of chemotherapy are no longer possible for this patient), and tumor genome analysis reveals abnormal activation of a cell signalling pathway that is targeted by a drug currently in clinical trials. If the patient is eligible for one of those clinical trials and the oncologist determines the trial would be appropriate for this patient, the patient could be encouraged to enroll.
Information revealed about an individual patient’s drug sensitivity (scenario “d”) might include whether that individual would be expected to rapidly or slowly metabolize certain anticancer drugs. Individuals with genetic variants associated with slower metabolism of a given drug will take longer to clear that drug from their body and require lower drug dose (to avoid accumulation of the drug and associated side effects); conversely, individuals with faster metabolism will require higher doses of the drug (to ensure sufficient drug exposure in the body to fight the tumor cells). Finally, if an individual has genetic variants that result in a seriously compromised ability to metabolize a given drug, that drug may be toxic and not suitable for administration to that individual. Presently, drug sensitivity screening before treatment is possible for several chemotherapy drugs (6-mercaptopurine, thioguanine, capecitabine, 5-fluorouracil, and irinotecan) and this list will likely expand dramatically in the future as more genome sequences are determined.