Intratumor Heterogeneity (aka, Things Have Many Parts)

To say that personalized medicine has hit a “bump in the road” with a study published this week in the New England Journal of Medicine reflects the expectancy that targeted drugs for cancer (or other diseases) ought to be around the corner. After all, now that we know that it’s possible to target the abnormal cellular mechanisms triggered by genetic mutations with laboratory-synthesized chemicals (Gleevec for CML, the recently approved Xalkori (generic name, crizotinib) for lung cancer), shouldn’t we just figure out the abnormalities in each kind of tumor and then create drugs to address whatever haywire situation results? Calling this study a “bump,” as the Wall Street Journal does, makes it seem as if this weren’t an entirely new field. No – this new study simply adds more to the story about genes and cancer.

Researchers from the UK’s Medical Research Council, Cancer Research UK, and other UK institutions, examined “intratumor heterogeneity.” That is, they looked at the amount of genetic variation within a single tumor. They found that more than 60% of the known somatic (ie, spontaneous, rather than inherited) genetic mutations were not present in every sample from a tumor. In other words, there is a lot of variety going on inside tumors.

That’s an enormous amount of variation. It means the odds that a tumor biopsy will contain the essential genetic information may be quite slim. It also points to the extraordinary capacity that tumors have to evolve rapidly, in part explaining why cancer often becomes resistant to whatever drug is attacking it.

The concern here is that if a researchers has a biopsy from one region of a tumor, the mutations present elsewhere in a tumor could be missed. The idea that a mutation could be seen in one sample and not another also adds another layer of difficulty to the task of sorting out which are the “driver” mutations—that is, which genetic mutations are triggering the cancer—and which mutations are more passive.

If you have tens of thousands of genes you’re working with in a particular tumor sample, sorting out the causative variations from the changes that happen as the tumor evolves is a long, arduous task. It’s for this reason that the idea of personalized medicine—and here we are talking specifically about drugs targeted against the genetic make-up of an individual cancer, not about a whole-person regimen for life based on your personal DNA quirks—is one that has to be held with a long-view. It took decades for the first useful chemotherapy drug to be discovered. If we absorb the notion that targeted therapy is still in its nascent stage, then this new study isn’t a bump in the road, but rather another description of the scenery.

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