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Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing — NEJM
Conclusions
Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through *Darwinian selection.
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* Synonym(s)
- Darwinian selection (natural selection)
Definition(s)
- Natural evolutionary process that results in the survival of organisms best suited to changing living conditions through the perpetuation of desirable genetic qualities and the elimination of undesirable ones.
Over the last ten years, there have been attempts to develop molecular-based tests to examine a broader range of "targeted" drugs. New technologies for measuring the expression (biological activity) of literally hundreds to thousands of genes as part of a single test. There are two main technologies involved: RT-PCR (reverse transcription polymerase chain reaction) and DNA microarray.
ReplyDeleteHence, the headlong rush to develop tests to identify molecular predisposing (meaning theoretical) mechanisms whose presence still does not guarantee that a targeted drug will be effective for an individual patient. Molecular testing methods detect the presence or the absence of selected gene or protein mutations which theoretically correlate with single agent drug activity. Cells are never even exposed to targeted agents. Genetic variations alone, do not determine response to targeted therapy.
These genetic profiles are able to help doctors determine which patients will probably develop cancer and those who will most likely relapse. However, when it comes to drug selection, the NCI has concluded it cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. It just tests for "theoretical" candidates for targeted therapy.
As you can see, searching for these genetic predispositions, it is like searching for a needle in a haystack. One can chase all the mutations they want, because if you miss just one, it may be the one that gets through. Or you can look for the drugs that are "sensitive" to killing all of your cancer cells, not theoretical candidates.
Human beings are demonstrably more than the sum of their genes. Cancer biology and the study of cancer therapy are many things, but simple is not one of them. Complex problems require solutions that incorporate all of their complexities, however uncomfortable this may be for genomic investigators.